DE60038686T2 - CONDENSED CYCLOHEPTAN AND CONDENSED AZACYCLOHEPTANE DERIVATIVES AND THEIR USE AS INTEGRIN RECEPTOR ANTAGONISTS - Google Patents

Abstract

The invention comprises novel compounds that are effective in the prophylaxis and treatment of diseases, such as integrin receptors mediated diseases, in particular, diseases or conditions mediated by integrin receptors, such as alphavbeta3, alphavbeta5, alphavbeta6 and the like. The invention encompasses novel compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of such diseases and disorders. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

Description

Background of the invention

The present invention comprises a new class of compounds which in the treatment of diseases, such as diseases, conditions or disorders, by integrin receptors, such as vitronectin and fibronectin receptors, be conveyed, are usable. In particular, the compounds of the invention and pharmaceutical compositions thereof for the Prophylaxis and treatment of diseases, conditions or disorders, atherosclerosis, restenosis, inflammation, cancer, osteoporosis and the like, usable. This invention also relates to intermediates and methods useful for preparing such compounds are.

integrins are heteromeric cell surface receptors, many of which are extracellular Have domains which bind to an Arg-Gly-Asp tripeptide (RDG) which is expressed in extracellular (plasma and matrix) proteins, such as fibronectin, vitronectin, fibrinogen and osteopontin. The fibrinogen receptor gpIIb / IIIa integrin is a platelet surface receptor, which is believed to promote platelet aggregation and formation of hemostatic Clots in the bleeding of wound sites (Blonde 71: 831, 1988).

Vitronectin receptors, α _v β ₃ and α _v β ₅ integrins are expressed by a number of cells, such as endothelial cells, smooth muscle cells, osteoclast cells, bone-resorbing cells, tumor cells and epithelial cells. Integrin α _v β ₃ has been reported to be involved in bone resorption (Endocrinology 137: 2347-54, 1996; J. Endocrinol. 154 (Suppl.): S47-S56, 1997), in cell binding, spreading and Walker (Int J Biochem Cell 31: 539-544, 1999, Carreitas et al., Int J Cancer 80: 285-294, 1999), in signal transduction, cell-to-cell interactions, and as Biochem Cell 29: 721-725, 1997), in tumor cell invasion, angiogenesis, wound healing, phagocytosis of apoptotic cells and inflammation (J. Cell Biol. 144: 767-775, J. Biol. 10: 456-461, 1997; Am J. Pathol 148: 1407-1421, 1996), in tumor growth and hypercalcemia of malignancy (Cancer Res. 58: 1930-1935, 1998), in which Tumorigenicity of human melanoma cells (Natali et al., Cancer Res. 57: 1554-60, 1997), in melanoma metastasis (Cancer Metastasis Rev. 14: 241-245, 1995; Cancer Metastasis Rev. 10: 3- 10, 1991), in the chondrocyte synthesis of matrix metalloproteinases (such as stromelysin, collagenase and gelatinase) involved in diseases such as rheumatoid arthritis and osteoarthritis (Arthritis Rheum. 38: 1304-1314, 1995), the progression of kidney damage in Fabry disease (Clin Chim Acta 279: 55-68, 1999) and viral infections (Virol J. 72: 3587-3594, 1998; Virology 203: 357-65, 1994). Keenan et al. (J. Med. Chem. 40: 2289-92, 1997) describe examples of α _v β ₃ inhibitors which are selective for α _v β ₃ over platelet fibrinogen receptor (α _IIb β ₃ ).

It is believed that integrin α _v β ₅ (Smith et al., J. Biol. Chem. 265: 11008-13, 1990) is involved in endocytosis and degradation of vitronectin (J. Biol. Chem. 268: 11492-5, 1993), the cellular movement of human keratinocytes (J. Biol. Chem. 269: 26926-32, 1994), tumor cell metastasis (J. Clin. Invest. 99: 1390-1398, 1997), the differentiation of Neuroblastoma metastasis (Am J. Pathol 150: 1631-1646, 1997) and viral infections (Nat Med Med (NY) 5: 78-82, 1999; J. Cell Biol. 127: 257-64, 1994).

Integrin α _v β ₆ is an RGD, tenascin and fibronectin binding protein (J. Biol. Chem. 267: 5790-6, 1992) expressed by a number of cells, such as carcinoma cells and epithelial cells, and it is believed that that it is involved in carcinoma cell proliferation (J. Cell Biol., 127: 547-56, 1994), in wound healing and cell binding (J. Invest. Dermatol., 106: 42-8, 1996), in epithelial inflammation, such as asthma (J. Cell Biol. 133: 921-928, 1996), in the induction of gelatinase B secretion, activation of the protein kinase C pathway, tumor cell proliferation and proliferation in colon cancer cells (Biochem. Biophys. Res. 249: 287-291, 1998; Int J Cancer 81: 90-97, 1999), in the regulation of pneumonia and fibrosis, and the binding and activation of transforming growth factor β1 (Munger et al., Cell (Cambridge, Mass ) 96: 319-328, 1999) and in viral infections (Virology 239: 71-77, 1997).

It has been reported that antagonists of vitronectin receptors α _v β ₃ , α _v β ₅ and / or α _v β ₆ in the treatment and prevention of atherosclerosis, restenosis, inflammation, wound healing, cancer (eg tumor regression by inducing apoptosis ), Metastasis, bone resorption-related diseases (e.g., osteoporosis), diabetic retinopathy, macular degeneration, angiogenesis and viral disease (e.g. WO 99/30713 ; WO 99/30709 ).

WO 99/05107 describes benzocycloheptenylacetic acid compounds useful as vitronectin receptor antagonists.

WO 98/14192 describes benzazepin-3-one-4-ylacetic acid compounds as vitronectin receptor antagonists.

WO 96/26190 describes benzodiazepine-3-one and benzazepine-3-onyiene bonds as integrin receptor inhibitors.

worin m, A, E, X¹, X², R², R³, R⁴, R⁶ und R⁷ wie hierin definiert sind, als Integrinrezeptor-Inhibitoren, insbesondere Fibrinogen-(α_IIbβ₃)- oder Vitronektin-(α_vβ₃)-Rezeptor-Inhibitoren verwendbar sind. WO 99/11626 describes compounds of the formula

wherein m, A, E, X ¹ , X ² , R ² , R ³ , R ⁴ , R ⁶ and R ^{7 are} as defined herein, as integrin receptor inhibitors, in particular fibrinogen (α _IIb β ₃ ) or vitronectin (α _v β ₃ ) receptor inhibitors are useful.

worin A₁, E, X¹, X², X³, R², R³, R⁴, R⁶ und R⁷ wie hierin definiert sind, als Integrinrezeptor-Inhibitoren, insbesondere Fibrinogen-(α_IIbβ₃)- oder Vitronektin-(α_vβ₃)-Rezeptor-Inhibitoren verwendbar sind. WO 97/01540 describes compounds of the formula

wherein A ₁ , E, X ¹ , X ² , X ³ , R ² , R ³ , R ⁴ , R ⁶ and R ^{7 are} as defined herein, as integrin receptor inhibitors, in particular fibrinogen (α _IIb β ₃ ) - or Vitronectin (α _v β ₃ ) receptor inhibitors are useful.

worin A, D, G, T, U, W und X wie hierin definiert sind, als Integrin-Inhibitoren von Fibrinogen-GPII_bIII_a verwendbar sind. US 5,565,449 describes compounds of the formula

wherein A, D, G, T, U, W and X are as defined herein, are useful as integrin inhibitors of fibrinogen GPII _b III _a .

US 5,705,890 describes tricyclic benzodiazepine compounds useful as platelet aggregation inhibitors (fibrinogen binding inhibitors).

US 5,674,865 describes benzodiazepindione compounds useful as platelet aggregation inhibitors (fibrinogen binding inhibitors).

WO 99/15178 and WO 99/15170 describe benzazepine acetic acid compounds useful as vitronectin receptor antagonists.

WO 99/11626 and WO 99/06049 describe tricyclic benzazepine, benzodiazepine acetate and benzazepine acetate compounds useful as fibrinogen and vitronectin receptor antagonists.

WO 99/15508 describes dibenzo [a, d] cyclohepten-10-acetic acid compounds useful as vitronectin receptor antagonists.

WO 99/15506 and WO 99/15507 describe iminobenzazole compounds useful as vitronectin receptor antagonists.

WO 98/18461 describes 4- to 10-membered mono- or polycyclic compounds having aromatic or non-aromatic ring systems (containing 0 to 4 oxygen, sulfur and / or nitrogen heteroatoms) which are useful as integrin receptor antagonists.

Where 97/01540 describes dibenzocyclohepten compounds useful as integrin receptor antagonists.

WO 96/26190 describes benzodiazepine-3-one and benzazepine-3-onyiene bonds useful as integrin receptor inhibitors.

Summary of the invention

The present invention encompasses a new class of compounds useful for the prophylaxis and treatment of diseases such as integrin receptor mediated diseases. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions mediated by integrin receptors such as α _v β ₃ , α _v β ₅ and α _v β ₆ . Accordingly, the invention also encompasses pharmaceutical compositions containing the compounds, methods for the prophylaxis and treatment of integrin receptor mediated diseases, such as cancer, tumor growth, metastasis, diabetic retinopathy, macular degeneration, angiogenesis, restenosis, bone resorption, atherosclerosis, inflammation, viral infection and wound healing Use of the compounds and compositions of the invention and intermediates and processes useful in preparing the compounds of the invention.

The compounds of the invention are represented by the following general structure: EB- (Alk) _p -Q- (Alk) _q -AG wherein E, B, Alk, Q, A, G, p and q are defined below.

The The foregoing summarizes only certain aspects of the invention, and it is neither intended nor should it be considered the invention limiting in any way be interpreted.

Detailed description of the invention

The present invention provides novel compounds useful for treating both disease states including cancer, tumor growth, metastasis, diabetic retinopathy, macular degeneration, angiogenesis, restenosis, bone resorption, atherosclerosis, inflammation, viral disease, and wound healing, as well as other disease states are associated with the same pathways causing said disease states, particularly those modulated by integrin receptors and related pathways such as the integrin receptors α _v β ₃ , α _v β ₅ and α _v β ₆ .

wobei jede Formel optional mit 1 bis 2 Resten R₂ substituiert ist; worin n 1 bis 4, bevorzugt 1 bis 3, bevorzugter 1 bis 2 ist; und
bevorzugter E -NH-C(NR₁)-R₃, -C(NR₁)-NH-R₃, -NH-C(NR₁)-NH-R₃ oder einen Rest der Formel bedeutet

wobei jede Formel optional mit 1 bis 2 Resten R₂ substituiert ist;
R₃ ein Aryl-, Arylalkyl-, Heteroaryl-, Heteroarylalkyl-, Heterocyclyl- oder Heterocyclylalkylrest ist, worin die Aryl-, Heteroaryl- und Heterocyclylreste optional mit 1 bis 3 Resten R₂ substituiert sind;
bevorzugt R₃ ein Aryl-, Aryl-C₁-C₁₀-alkyl-, Heteroaryl-, Heteroaryl-C₁-C₁₀-alkyl-, Heterocyclyl- oder Heterocyclyl-C₁-C₁₀-alkylrest ist, worin die Heteroaryl- und Heterocyclylreste 5 bis 15 Ringglieder haben und die Aryl-, Heteroaryl- und Heterocyclylreste optional mit 1 bis 3 Resten R₂ substituiert sind;
bevorzugter R₃ ein Aryl-, Aryl-C₁-C₄-alkyl-, Heteroaryl-, Heteroaryl-C₁-C₄-alkyl-, Heterocyclyl- oder Heterocyclyl-C₁-C₄-alkylrest ist, worin die Heteroaryl- oder Heterocyclylreste 5 bis 15 Ringglieder haben und die Aryl-, Heteroaryl- und Heterocyclylreste optional mit 1 bis 3 Resten R₂ substituiert sind;
bevorzugter R₃ ein Aryl-, Aryl-C₁-C₄-alkyl-, Heteroaryl- oder Heteroaryl-C₁-C₄-alkylrest ist, worin der Heteroarylrest 5 bis 15 Ringglieder hat und die Aryl- und Heteroarylreste optional mit 1 bis 3 Resten R₂ substituiert sind;
bevorzugter R₃ ein Heteroarylrest mit 5 bis 15 Ringgliedern ist und optional mit 1 bis 3 Resten R₂ substituiert ist;
am bevorzugtesten R₃ ein Heteroarylrest mit 5 bis 10 Ringgliedern ist und optional mit 1 bis 3 Resten R₂ substituiert ist;
G ein Rest der Formeln

ist, worin W₁ C-R₁₅ oder N ist, W₂ C-R₁₆ oder N ist, W₃ C-R₁₇ oder N ist und W₄ C-R₁₈ oder N ist, mit der Maßgabe, dass nicht mehr als 2 von W₁, W₂, W₃ oder W₄ N bedeuten;
bevorzugter G ein Rest der Formel

ist; oder
alternativ bevorzugter G ein Rest der Formel

ist.According to the present invention compounds of the formula EB- (Alk) _p -Q- (Alk) _q -AG or a pharmaceutically acceptable salt thereof, wherein p and q are each independently 0 or 1;
each alk is independently an alkyl group, preferably a C ₁ -C ₁₂ alkyl group, more preferably a C ₁ -C ₈ alkyl group and most preferably a C ₁ -C ₆ alkyl group;
A and Q are each independently a bond, -C (X) -, -S (O) _t -, -S-, -O-, -N (R ₁ ) -, -C (Y) -N (R ₁ ) -, --N (R ₁ ) -C (Y) -, -S (O) _t --N (R ₁ ) -, --N (R ₁ ) -S (O) _t -, --N (R ₁ ) - C (Y) -N (R ₁ ) - or -N (R ₁ ) -S (O) _t -N (R ₁ ) - or a radical cycloalkyl, aryl, heterocyclyl or heteroaryl, each optionally having 1 to 3 R _{2 is} substituted;
A and Q each independently represents a bond, -C (X) -, -S (O) _t -, -S-, -O-, -N (R ₁ ) -, -C (Y) -N (R ₁ ), -N (R ₁ ) -C (Y) -, -S (O) t N (R ₁ ) -, -N (R ₁ ) -S (O) _t -, -N (R ₁ ) -C (Y) -N (R ₁ ) - or -N (R ₁ ) -S (O) _t -N (R ₁ ) - or a radical C ₃ -C ₈ -cycloalkyl, aryl, heterocyclyl with 5 to 8 ring or heteroaryl having 5 to 10 ring members, each of which is optionally substituted with 1 to 3 R ₂ radicals; and
More preferably, A and Q are each independently a -C bond (O) -, -S (O) _t -, -O-, -N (R ₁ ) -, -C (Y) -N (R ₁ ) -, -N (R ₁ ) -C (Y) -, -S (O) t N (R ₁ ) - or -N (R ₁ ) -S (O) _t - or a radical C ₃ -C ₈ -cycloalkyl, phenyl, heterocyclyl with 5 to 6 ring members or heteroaryl with 5 to 6 ring members, each of which is optionally substituted with 1 to 3 R ₂ radicals; and
B is a bond -C (Y) -, -S (O) _t -, -S-, -O-, - (N (R ₁ ) -, -C (Y) -N (R ₁ ) -, -N (R ₁ ) -C (Y) -, -S (O) _t -N (R ₁ ) -, -N (R ₁ ) -S (O) _t -, -N (R ₁ ) -C (Y) -N (R ₁ ) - or -N (R ₁ ) -S (O) _t -N (R ₁ ) - or a radical cycloalkyl, aryl, heterocyclyl or heteroaryl, each optionally substituted with 1 to 3 radicals R ₂ is;
B is preferably a bond, -C (Y) -, -S (O) _t -, -S-, -O-, -N (R ₁ ) -, -C (Y) -N (R ₁ ) -, - N (R ₁ ) -C (Y) -, -S (O) _t -N (R ₁ ) -, -N (R ₁ ) -S (O) _t -, -N (R ₁ ) -C (Y ) -N (R ₁ ) - or -N (R ₁ ) -S (O) t N (R ₁ ) - or a radical C ₃ -C ₈ acyloalkyl, aryl, heterocyclyl having 5 to 8 ring members or heteroaryl with 5 to 10 ring members, each of which is optionally substituted with 1 to 3 R _2's ;
more preferably B is a bond, -C (Y) -, -S (O) _t -, -O- or -N (R ₁ ) - or a radical phenyl, heterocyclyl having 5 to 6 ring members or heteroaryl having 5 to 6 ring members each of which is optionally substituted with 1 to 3 R ₂ radicals; and
most preferably B is a bond, -S (O) _t -, -O- or -N (R ₁ ) - or a phenyl radical which is optionally substituted with 1 to 3 radicals R ₂ ;
with the proviso that the total number of atoms directly connecting E to G over the shortest sequence is 3 to 12, preferably 4 to 9, more preferably 4 to 7;
each X is independently O or S and preferably O;
each Y is independently O, S, N (R ₁ ) or N (CN) and preferably O, N (R ₁ ) or N (CN);
each t is independently 1 or 2 and preferably 2;
each R _{1 is} independently hydrogen or alkyl, preferably each R _{1 is} independently hydrogen or C ₁ -C ₄ alkyl, and most preferably each R _{1 is} independently hydrogen or methyl;
each R ₂ is independently a halogen atom, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, hydroxy, carboxy, cyano, azido, amidino, guanidino, nitro, amino, alkylamino, or dialkylamino radical or two adjacent radicals R _{2 represent} a methylenedioxy, ethylenedioxy or propylenedioxy radical;
R ₂ preferably each independently represents a halogen atom, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ haloalkyl having 1 to 3 halo radicals , C ₁ -C ₄ -haloalkoxy- having 1 to 3 halogen radicals, hydroxy, carboxy, cyano, azido, amidino, guanidino, nitro, amino, C ₁ -C ₄ -alkylamino or di ( C ₁ -C ₄ ) alkylamino radical or two adjacent radicals R _{2 is} a methylenedioxy, ethylenedioxy or propylenedioxy radical;
more preferably, the radicals R _{2 are} each independently halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, -CF ₃ -, -OCF ₃ -, hydroxy-, Cyano, nitro, amino, C ₁ -C ₄ alkylamino or di (C ₁ -C ₄ alkyl) amino; and
most preferably the radicals R _{2 are} each independently a halogen atom, methyl, methoxy, -CF ₃ , -OCF ₃ , hydroxy, cyano, nitro, C ₁ -C ₄ alkylamino or di (C ₁ -) C ₂ alkyl) amino group;
E is an -R ₃ -, -NH-R ₃ -, -NH-C (Y) -R ₃ -, -C (Y) -NH-R ₃ -, -NH-S (O) _t -R ₃ - , -S (O) _t -NH-R ₃ -, -NH-C (Y) -NH-R ₃ -, -NH-C (Y) -OR ₃ -, -NH-S (O) _t -NH R ₃ , -NH-alkyl-C (Y) -R ₃ -, -NH-alkyl-S (O) _t -R ₃ -, -NH-alkyl-C (Y) -NH-R ₃ - or -NH-alkyl-S (O) _t -NH-R ₃ radical;
E preferably represents an -R ₃ -, -NH-R ₃ -, -NH-C (Y) -R ₃ -, -C (Y) -NH-R ₃ -, -NH-S (O) _t -R ₃ -, -S (O) _t -NH-R ₃ -, -NH-C (Y) -NH-R ₃ -, -NH-C (Y) -OR ₃ -, -NH-S (O) _t - NH-R ₃ -, -NH- (C ₁ -C ₄ -alkyl) -C (Y) -R ₃ -, -NH- (C ₁ -C ₄ -alkyl) -S (O) _t -R ₃ - , -NH- (C ₁ -C ₄ -alkyl) -C (Y) -NH-R ₃ - or -NH- (C ₁ -C ₄ -alkyl) -S (O) _t -NH-R ₃ -Rest means;
more preferably E is -R ₃ -, -NH-R ₃ -, -NH-C (Y) -R ₃ -, -C (Y) -NH-R ₃ -, -S (O) t -NH-R ₃ -, -NH-C (Y) -NH-R ₃ -, -NH-C (Y) -OR ₃ - or -NH- (C ₁ -C ₄ -alkyl) -C (Y) -NH-R ₃ Radical means;
more preferably E is -R ₃ -, -NH-R ₃ -, -NH-C (Y) -R ₃ -, -C (Y) -NH-R ₃ -, -NH-C (Y) -NH-R ₃ - or -NH-C (Y) -OR ₃ radical; and
most preferably E is an -R ₃ -, -NH-R ₃ -, -NH-C (NR ₁ ) -R ₁ -, -C (NR ₁ ) -NH-R ₁ -, -NH-C (NR ₁ ) -NH-R ₁ or -NH-C (NR ₁ ) -O-CH ₃ radical; or
alternatively preferably E is -NH-C (NR ₁ ) -R ₃ , -C (NR ₁ ) -NH-R ₃ , -NH-C (NR ₁ ) -NH-R ₃ or a radical of the formula

wherein each formula is optionally substituted with 1 to 2 R ₂ radicals; wherein n is 1 to 4, preferably 1 to 3, more preferably 1 to 2; and
more preferably E is -NH-C (NR ₁ ) -R ₃ , -C (NR ₁ ) -NH-R ₃ , -NH-C (NR ₁ ) -NH-R ₃ or a radical of the formula

wherein each formula is optionally substituted with 1 to 2 R ₂ radicals;
R _{3 is} an aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl radical, wherein the aryl, heteroaryl and heterocyclyl radicals are optionally substituted with 1 to 3 R ₂ radicals;
R _{3 is} preferably an aryl, aryl-C ₁ -C ₁₀ -alkyl, heteroaryl, heteroaryl-C ₁ -C ₁₀ -alkyl, heterocyclyl or heterocyclyl-C ₁ -C ₁₀ -alkyl radical in which the heteroaryl and heterocyclyl radicals have 5 to 15 ring members and the aryl, heteroaryl and heterocyclyl radicals are optionally substituted by 1 to 3 radicals R ₂ ;
more preferably R _{3 is} an aryl, aryl-C ₁ -C ₄ -alkyl, heteroaryl, heteroaryl-C ₁ -C ₄ -alkyl, heterocyclyl or heterocyclyl-C ₁ -C ₄ -alkyl radical in which the heteroaryl or heterocyclyl radicals have 5 to 15 ring members and the aryl, heteroaryl and heterocyclyl radicals are optionally substituted by 1 to 3 radicals R ₂ ;
more preferably R _{3 is} an aryl, aryl, C ₁ -C ₄ alkyl, heteroaryl or heteroaryl C ₁ -C ₄ alkyl radical, wherein the heteroaryl radical has from 5 to 15 ring members and the aryl and heteroaryl radicals optionally with 1 to 3 R ₂ radicals are substituted;
more preferably R _{3 is} a heteroaryl group having 5 to 15 ring members and is optionally substituted with 1 to 3 R ₂ groups;
most preferably R _{3 is} a heteroaryl group having 5 to 10 ring members and is optionally substituted with 1 to 3 R ₂ groups;
G is a remainder of the formulas

wherein W _{1 is} CR ₁₅ or N, W _{2 is} CR ₁₆ or N, W _{3 is} CR ₁₇ or N and W _{4 is} CR ₁₈ or N, with the proviso that not more than 2 of W ₁ , W ₂ , W ₃ or W ₄ N;
more preferably G is a radical of the formula

is; or
alternatively more preferably G is a radical of the formula

is.

worin W₁ C-R₁₅ ist, W₂ C-R₁₆ ist, W₃ C-R₁₇ ist und W₄ C-R₁₈ ist.Alternatively, G is a radical of the formula

wherein W _{1 is} CR ₁₅ , W _{2 is} CR ₁₆ , W _{3 is} CR ₁₇ , and W _{4 is} CR ₁₈ .

The radicals R ₁₅ , R ₁₇ and R ₁₈ are each independently a hydrogen atom, halo, hydroxy, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, -CF ₃ - or -OCF _3- residue; and
most preferably R ₁₅ , R ₁₇ and R _{18 are} each independently a hydrogen, fluoro, chloro, bromo, hydroxy, cyano, methyl, methoxy, -CF ₃ or -OCF ₃ radical; and
R _{16 is} hydrogen, halogen, hydroxy, carboxy, cyano, amino, -R ₉ , -S (O) _t -R ₉ , -OR ₉ , -N (R ₁ ) -R ₉ , -C ( O) -N (R ₁ ) -R ₉ , -N (R ₁ ) -C (O) -H, -N (R ₁ ) -C (O) -R ₉ , -S (O) _t -N ( R ₁ ) -R ₉ or -N (R ₁ ) -S (O) _t -R ₉ ; and
most preferably R _{16 is} hydrogen, fluoro, chloro, bromo, hydroxy, cyano, amino, R ₉ , -S (O) _t -R ₉ , -OR ₉ , -N (R ₁ ) -R ₉ , -C (O) -N (R ₁ ) -R ₉ , -N (R ₁ ) -C (O) -H, -N (R ₁ ) -C (O) -R ₉ , -S (O ) _{t is} -N (R ₁ ) -R ₉ or -N (R ₁ ) -S (O) _t -R ₉ ;
with the proviso that the combined total number of aryl, cycloalkyl, heteroaryl and heterocyclyl radicals in R ₁₅ , R ₁₆ , R ₁₇ and R _{18 is} 0 to 1;
each R _{9 is} independently a C ₁ -C ₄ alkyl, -CF ₃ , phenyl C ₁ -C ₄ alkyl or phenyl radical wherein each phenyl radical is optionally substituted with 1 to 3 R ₂ radicals; and
most preferably each R _{9 is} independently a C ₁ -C ₄ alkyl, -CF ₃ , phenyl C ₁ -C ₂ alkyl or phenyl radical wherein each phenyl radical is optionally substituted with 1 to 3 R ₂ radicals;
X ₂ , X ₃ and X _{6 are} each independently a -CHR ₆ radical,
Z _{1 is} CR ₆ ;
R ₁₀ and R _{12 are} each independently hydrogen, hydroxy or C ₁ -C ₂ alkyl; most preferably R ₁₀ and R _{12 are} each hydrogen;
with the proviso that the combined total number of aryl, heteroaryl and heterocyclyl radicals in X ₂ , X ₃ , X ₆ , R ₁₀ and R _{12 is} 0 to 2, preferably 0 to 1;
each R _{6 is} independently hydrogen, hydroxy or C ₁ -C ₂ alkyl and most preferably each R _{6 is} hydrogen; and
each R _{7 is} independently a phenyl, phenyl C ₁ -C ₂ alkyl, heteroaryl, heteroaryl C ₁ -C ₂ alkyl, heterocyclyl or heterocyclyl C ₁ -C ₃ alkyl radical, each of optionally substituted with 1 to 3 R ₂ , and wherein the heteroaryl and heterocyclyl groups have 5 to 6 members; and
R _{4 is} a C ₁ -C ₄ alkyl radical substituted with a carboxy, tetrazolyl or -CO ₂ R ₈ radical and optionally substituted with an aryl, heteroaryl or heterocyclyl radical, each of which is optional is substituted with 1 to 3 radicals R ₂ ,
more preferably R _{4 is} a C ₁ -C ₄ alkyl radical substituted with a carboxy or -CO ₂ R ₈ radical; and most preferably R _{4 is} a C ₁ -C ₂ alkyl radical substituted with a carboxy or -CO ₂ R ₈ radical;
R _{8 is} a C ₁ -C ₄ alkyl radical which is optionally substituted with an aryl or heteroaryl radical having 5 to 10 ring members, wherein the aryl and heteroaryl radicals are optionally substituted with 1 to 3 R ₂ radicals;
more preferably R _{8 is} a C ₁ -C ₄ alkyl radical optionally substituted with a phenyl radical wherein the phenyl radical is optionally substituted with 1 to 3 R ₂ radicals; and most preferably R _{8 is} a C ₁ -C ₂ alkyl radical.

In Another aspect is the use of the above compounds for the manufacture of a medicament for therapeutic or prophylactic Treatment of disease states, where tumor growth, metastasis, diabetic retinopathy, macular degeneration, Angiogenesis, restenosis, bone resorption, atherosclerosis, inflammation, viral Disease or wound healing involved.

In a further embodiment The invention relates to the use of the above compounds for the preparation of a medicament for modulation, preferably inhibition, one or more integrin receptors provided.

In a further embodiment The invention relates to the use of the above compounds for the preparation of a medicament for modulation, preferably inhibition, one or more vitronectin receptors provided.

In a related embodiment, there is provided the use of the above compounds for the manufacture of a medicament for modulating, preferably inhibiting, α _v β ₃ and / or α _v β ₅ and / or α _v β ₆ receptors.

An additional preferred embodiment of the invention comprises the use of the above compounds for the manufacture of a medicament for the therapeutic or prophylactic treatment of an integrin receptor mediated disease state. So z. For example, the compounds of the invention modulate a reaction mediated by an integrin receptor, e.g. By antagonizing one or more vitronectin receptor responses. Particularly preferred in this embodiment is the inhibition of the α _v β ₃ and / or α _v β ₅ and / or α _v β ₆ receptor reaction.

The compounds and pharmaceutical compositions of this invention are useful for use in the prophylaxis and / or treatment (comprising administration to a warm-blooded animal, such as a mammal (e.g., a human, horse, sheep, pig, mouse, rat and bovine), an effective amount of such a compound or composition); and (1) diseases and disorders caused or facilitated by modulating one or more integrin receptors, such as by antagonizing one or more integrin receptors, including, but not limited to, disorders caused by or multiple integrin receptors are induced or relieved; (2) diseases and disorders caused or facilitated by modulating one or more vitronectin receptors, such as by antagonizing one or more vitronectin receptors, including, but not limited to, disorders induced or facilitated by one or more vitronectin receptors; (3) Disorders and disorders caused or facilitated by modulating the α _v β ₃ and / or α _v β ₅ and / or α _v β ₆ receptor response, such as by inhibiting the α _v β ₃ - and / or α _v β ₅ and / or α _v β ₆ receptor reactions, including, but not limited to, interferences caused by the α _v β ₃ and / or α _v β ₅ and / or α _v β ₆ receptor response can be induced or relieved; or (4) disease states involving cancer such as tumor growth, metastasis, diabetic retinopathy, macular degeneration, angiogenesis, restenosis, bone resorption such as osteoporosis, osteoarthritis, bone formation, bone loss, hyperparathyroidism, Paget's disease malignancy, osteolytic lesions, Behcet's disease, osteomalacia, hyperostosis or osteoperosis, atherosclerosis, inflammation such as rheumatoid arthritis, pain, psoriasis or allergies, viral disease or wound healing.

As used herein, the following terms are intended to have the following meanings:
"Alkyl", alone or in combination, means a saturated or partially unsaturated (provided that at least two carbon atoms are present) straight-chain or branched-chain alkyl radical containing the indicated number of carbon atoms, preferably 1 to 18 carbon atoms (C ₁ -C ₁₈ ), more preferably 1 to 12 carbon atoms (C ₁ -C ₁₂ ), more preferably 1 to 8 carbon atoms (C ₁ -C ₈ ), more preferably 1 to 6 carbon atoms (C ₁ -C ₆ ), more preferably 1 to 4 carbon atoms (C ₁ -C ₄ ), more preferably 1 to 3 carbon atoms (C ₁ -C ₃ ) and most preferably 1 to 2 carbon atoms (C ₁ -C ₂ ). Examples of such radicals include methyl, ethyl, vinyl, n-propyl, allyl, isopropyl, n-butyl, 1-butenyl, 2-butenyl, 3-butenyl, sec-butyl, sec-butenyl, t-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 3-methylbutenyl, n -hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. A partially unsaturated alkyl preferably has at least one double or triple bond, more preferably 1 to 3 double or triple bonds, more preferably 1 to 2 double or triple bonds, and most preferably one double bond or one triple bond. "Alkyl" may also mean a divalent alkyl radical such as arylalkyl.

"Alkoxy", alone or in Combination means a radical of the type "R-O-", wherein "R" is an alkyl radical as above is defined, and "O" is an oxygen atom is. Examples of such alkoxy radicals include ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and allyloxy.

"Alkylthio", alone or in Combination means a radical of the type "R-S-", wherein "R" is an alkyl radical, such as as defined above, and "S" is a sulfur atom is. Examples of such alkylthio radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio and allylthio.

Of the Term "carbocyclic", alone or in Combination, refers to an organic cyclic component, in which the cyclic scaffold consists only of carbon atoms, while the term "heterocyclic", alone or in Combination, referring to an organic cyclic component, in which the cyclic scaffold one or more, preferably 1 to 4, more preferably 1 to 3, most preferably 1 to 2, contains heteroatoms, selected from nitrogen, oxygen or sulfur, and the carbon atoms contain or may not contain.

The term "cycloalkyl", alone or in combination, refers to a saturated or partially unsaturated (preferably 1 to 2 double bonds, more preferably a double bond) carbocyclic component containing the indicated number of carbon atoms, preferably 3 to 12 ring members, more preferably 3 to 8 ring members, and most preferably 3 to 6 ring members. So z. For example, the term "C ₃ -C ₁₀ cycloalkyl" refers to an organic cyclic substituent in which 3 to 10 carbon atoms form a three, four, five, six, seven, eight, nine or ten membered ring including z. A cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cyclohexyl, cycloheptyl and cyclooctyl ring. As used herein, "cycloalkyl" may also refer to two or more cyclic ring systems which have been fused to form bicyclic, tricyclic or other similar bridging compounds (e.g., norbornanyl, norbornenyl, adamantyl, etc.).

"Aryl" refers to an aromatic carbocyclic group having a single ring, e.g. As a phenyl ring, several rings, z. B. biphenyl or more condensed rings in which at least one ring is aromatic, for. Naphthyl, 1,2,3,4-tetrahydronaphthyl, anthryl or phenanthryl unsubstituted or having one or more (preferably 1 to 5, preferably 1 to 4, more preferably 1 to 3, most preferably 1 to 2) other substituents , as defined above, may be substituted. The substituents attached to a phenyl ring portion of an aryl moiety in the compounds of this invention may be located in the ortho, meta or para orientations. Examples of typical aryl moieties included within the scope of the present invention may include, but are not limited to, the following:

"Arylalkyl", alone or in combination, means an alkyl radical as defined above wherein a hydrogen atom is replaced by an aryl radical, such as benzyl, and e.g. For example, "aryl-C ₁ -C ₄ -alkyl", alone or in combination, means a C ₁ -C ₄ -alkyl radical as defined above, wherein a hydrogen atom is replaced by an aryl radical.

"Heterocycle" refers to a saturated, unsaturated or aromatic carbocyclic group with a single ring, several rings or more condensed rings and at least a heteroatom, such as nitrogen, oxygen or sulfur, in at least one of the rings. "Heteroaryl" refers to a heterocycle in which at least one ring is aromatic. Next you can bi- or tricyclic heteroaryl components at least one ring included, either completely or partially saturated is. Each of the heteroaryl groups can be unsubstituted or optional with one or more groups as defined above, and one or more, preferably 1 to 2, more preferably one, "oxo" group substituted be. "Heterocyclyl" refers to a saturated one or partially unsaturated, preferably a double bond, monocyclic or bicyclic, preferably monocyclic, heterocycle radical which is at least one, preferably 1 to 4, more preferably 1 to 3, more preferably 1 to 2, nitrogen, Contains oxygen or sulfur atom ring members, and preferably 3 to 8 ring members in each ring, more preferably 5 to 8 ring links in each ring and still more preferably 5 to 6 ring members in each ring. "Heterocyclyl" is intended to mean sulfone and sulfoxide derivatives of sulfur ring members and N-oxides of tertiary nitrogen ring members and carbocyclic condensed, preferably 3 to 6 ring carbon atoms and more preferably 5 to 6 ring carbon atoms. Each of the Heterocyclyl groups can be unsubstituted or optionally with a or more groups as defined above, and one or more a plurality, preferably 1 to 2, more preferably one, "oxo" group be substituted.

Of the One skilled in the art will recognize that heterocycle components are isomeric in some Can exist forms, which are all encompassed by the present invention. So z. For example, a 1,3,5-triazine moiety isomeric to a 1,2,4-triazine group. Such positional isomers are within the scope of the present invention to take into account. In the same way you can the heterocyclyl or heteroaryl groups to other components in be bound to the compounds of the invention. The binding point or the binding points to these other components is or are not to be construed as limiting the scope of the invention. Therefore, can z. B. a pyridyl component to other groups through the 2-, 3- or 4-position of the pyridyl group, and a piperidinyl may be attached to other groups through the nitrogen or carbon atoms be bound to the piperidinyl group. All such configurations are to be construed as being within the scope of the present invention.

Examples of heterocyclic or heteroaryl moieties encompassed by the scope of the present invention may include, but are not limited to, the following:

Heterocycle "condensed" forms a ring system, in which a heterocyclyl or heteroaryl group and a cycloalkyl or aryl group have two carbon atoms in common, e.g. Indol, Isoquinoline, tetrahydroquinoline and methylenedioxybenzene.

"Benzo", alone or in combination, means a benzene-derived divalent radical C ₆ H ₄ . "Benzo fused" forms a ring system in which benzene and a cycloalkyl or aryl group share two carbon atoms, e.g. B. tetrahydronaphthylene.

Of the The term "halo" or "halogen" refers to a halogen atom which may include fluorine, chlorine, bromine and iodine. preferred Halogen groups include chlorine, bromine and fluorine, with chlorine and fluorine are particularly preferred.

"Haloalkyl", alone or in Combination means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1 to 3, by a halogen atom, preferably fluorine or chlorine atoms, is replaced. Examples of such haloalkyl radicals include 1,1,1-trifluoroethyl, Chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl and bis (trifluoromethyl) methyl.

The following table defines by way of example certain ring structure abbreviations used herein:

Certain symbols used herein are intended to have the following meanings:

und obwohl eine Form hierin genannt, beschrieben, gezeigt und/oder beansprucht ist, sollen alle tautomeren Formen inhärent in einer solchen Bezeichnung, Beschreibung, Wiedergabe, und/oder einem solchen Anspruch umfasst sein.It should be understood that compounds of the invention may contain groups that may exist in tautomeric forms, such as cyclic and acyclic amidine and guanidine groups, heteroatom substituted heteroaryl groups (Y = O, S, NR), and the like

and although a form is mentioned, described, shown and / or claimed herein, all tautomeric forms are to be inherently encompassed within such description, description, reproduction, and / or claim.

"Modulating" as used herein refers to the ability of a compound of this invention to interact with a receptor, a target gene or another gene product to (a) enhance the activity of that receptor, target gene or other gene product or biological activity (e.g. As an agonist) or (b) control the receptor, target gene or other gene product or biological effect, in particular by acting as an antagonist to the receptor, the target gene or the other gene product. In addition, "modulating" includes the ability of a compound of the invention to effect a desired biological response, even if that reaction occurs upstream or downstream of one or more steps in a signaling pathway from the particular receptor, target gene, or other gene product. So z. For example, the compounds of the invention provide the desired effect by interacting with an integrin receptor, particularly a vitronectin receptor such as the α _v β ₃ and / or α _v β ₃ and / or α _v β ₆ receptor, to act as an agonist or Antagonist to this receptor or at some point, either upstream or downstream in the signaling pathway for the receptor to act to effect the desired therapeutic or prophylactic reaction.

"Pharmaceutically acceptable Salt, "as here used, refers to an organic or inorganic salt, which is useful in the treatment of a warm-blooded animal. Such Salts can Acid addition salts or basic addition salts, depending on the nature of the compound this invention. For Examples of "pharmacological acceptable salts "cf. Berge et al., J. Pharm. Sci. 66: 1 (1977). As used herein "Warmblood" includes a mammal, including one Member of the family of the human, the horse, the pig, of the bovine, the mouse, the dog and the cat.

In the case of an acidic component in a compound of this invention may be a salt by treatment of a compound of this invention with a basic compound, especially an inorganic one Base, to be formed. Preferred inorganic salts are those with alkali and alkaline earth metals, such as lithium, sodium, potassium, Barium and calcium are formed. Preferred salts with organic bases include, for. Ammonium, dibenzylammonium, 2-hydroxyethylammonium, Bis (2-hydroxyethyl) ammonium, phenylethylbenzylamine and dibenzylethylenediamine salts. Other salts of acidic components may e.g. B. include such salts, which are formed with procaine, quinine and N-methylglucosamine, and Salts with basic amino acids, such as glycine, ornithine, histidine, phenylglycine, lysine and arginine, are formed. A particularly preferred salt is a sodium or Potassium salt of a compound of this invention.

With Regarding basic components will be a salt through the treatment a compound of this invention with an acidic compound, in particular an inorganic acid, educated. Preferred inorganic salts of this type may, for. As the hydrochloric, hydrobromic, hydrogen iodide, sulfur or Phorphorsäuresalze include. Preferred organic salts of this type may, for. Salts with formic, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, d-glutamic, d-camphorsic, glutaric, glycolic, phthalic, tartaric, lauric, stearic, salicylic , Methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sorbic acid, purine acid, benzoic acid and cinnamic acid are formed. A particularly preferred salt of this type is a Hydrochloride or sulfate salt of a compound of this invention.

Also includes pharmaceutically acceptable esters of a carboxylic acid or Hydroxyl-containing group, including a metabolically labile Ester or a prodrug form of a compound of this invention. A metabolically labile ester is an ester, the z. B. an increase in blood tests and the efficacy of the corresponding can extend the non-esterified form of the compound. A prodrug form is a form that is not an active form of the administered molecule, but after some in vivo activity or biotransformation, such as Metabolism, eg. As enzymatic or hydrolytic cleavage, therapeutic becomes active. In terms of for a general discussion of prodrugs comprising esters, cf. Svensson and Tunek, Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985).

Examples of a masked carboxylate anion include a variety of esters such as alkyl (e.g., methyl, ethyl), cycloalkyl (e.g., cyclohexyl), aralkyl (e.g., benzyl, p -methoxybenzyl), and alkylcarbonyloxyalkyl (e.g. pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl-substituted derivatives which are cleaved by esterases in vivo to release the free drug and formaldehyde (Bungaard, J. Med. Chem. 2503 (1989)). Agents containing an acidic NH group, such as imidazole, imide and indole, have also been masked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 4/11/81) describe Mannich base hydroxamic acid prodrugs, their preparation and use. Esters of a compound of this invention may e.g. Both methyl, ethyl, propyl and butyl esters, as well as other suitable esters formed from an acidic component and a hydroxyl-containing component, may be included. Metabolically labile esters may, for. For example, methoxymethyl, ethoxymethyl, isopropoxymethyl, α-methoxyethyl, groups such as α- (C ₁ -C ₄ ) alkoxy) ethyl, z. Methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, etc., 2-oxo-1,3-dioxolen-4-ylmethyl groups such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, etc., C ₁ - C ₃ alkylthiomers thyl groups, eg. Methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, etc., acyloxymethyl groups, e.g. Pivaloyloxymethyl, α-acetoxymethyl, ethoxycarbonyl-1-methyl or α-acyloxy-α-substituted methyl groups, e.g. For example, α-acetoxyethyl.

In addition, the Compounds of the invention one or more asymmetric carbon atoms and therefore exist in stereoisomeric forms. All stereoisomers should be included within the scope of the present invention. As used, "stereoisomer" or "stereoisomer" refers to a compound, the same molecular weight, the same chemical composition and the same constitution has as another connection where but the atoms are so copied that their orientation in the three-dimensional Space is different. Such stereoisomers can be used as enantiomeric mixtures, Diastereomers are present or can into individual stereoisomeric components (eg specific enantiomers) separated by methods known to those skilled in the art.

In same way the compounds of this invention are present as isomers, i. H. links the same molecular formula, but in which the atoms are relative arranged differently from each other. The person skilled in the art is aware that it is possible is to produce Verbindun gene of this invention, in which one or more of the substituents are reversed relative to the other atoms in the molecule are arranged. This means, the one to be introduced Substituent may be the same as the one mentioned with the exception that he is in the molecule introduced in reverse orientation. The person skilled in the art recognizes that these isomeric forms of the compounds of this invention as to be construed within the scope of the present invention.

Further can the compounds of the invention are present as crystalline solids, the usual Solvents such as ethanol, N, N-dimethylformamide or water can. Therefore, you can crystalline forms of the compounds of the invention as solvates and / or Hydrates of the parent compounds or their pharmaceutically acceptable Salts are present. All such forms are equally as in the Falling interpreted area of the invention.

Even though it possible may be to administer a compound of the invention alone, In the described methods, the compound administered is normally as an active ingredient in a pharmaceutical formulation available. In another embodiment The invention therefore provides a formulation comprising a Compound of this invention in combination with a pharmaceutical acceptable carrier, thinner or excipiens for that contains.

The composition used in said therapeutic methods can be in a variety of forms. These include z. B. solid, semi-solid and liquid Dosage forms, such as tablets, pills, powders, liquid solutions or suspensions, liposomes, injectable and infusible solutions. The preferred form depends of the intended mode of administration and therapeutic Application. considerations for preparing suitable formulations are known in the art and are z. In Goodman and Gilman's: "The Pharmacological Basis of Therapeutics, 8th ed., Pergamon Press, Gilman et al., eds. (1990) and Remington's Pharmaceutical Sciences ", 18th ed., Mack Publishing Co., A. Gennaro, Hersg. (1990). method for administration are discussed therein, e.g. For oral, topical, intravenous, intraperitoneal or intramuscular Administration. Pharmaceutically acceptable carriers, diluents and excipients are equally discussed in it. Typical carriers, diluents and excipients may be water (eg water for injection), buffer, lactose, starch and sucrose.

As As noted, a compound of the invention may be administered orally, topically or parenterally (eg intravenously, intraperitoneal, intramuscular, administered subcutaneously) or as a dry powder, aerosol or atomization for pulmonary Administration are inhaled. Such forms of the compounds of Invention can by usual measures for producing aerosols or for administering dry powder medications using devices such. B. metered dose inhalers, Nasal spray, Dry powder inhalers, fogging devices or ultrasonic fogging devices, be administered. Such devices may optionally be adapted to an opening mouthpiece contain. In some cases it may be desirable the desired one Compound of the invention by continuous infusion, such as by a continuous infusion pump or using a transdermal delivery device, such as a pillow.

The compounds of the invention may also be administered as an aerosol. The term "aerosol" includes any suspended phase of a gas-based compound of the invention which is capable of being inhaled into the bronchioles or nasal passages. Specifically, aerosol comprises a suspension of droplets the desired gas-based compound as can be made in a metered-dose inhaler or nebulizer or mist sprayer. Aerosol also includes a dry powder composition of a compound of the present invention suspended in air or other carrier gas, e.g. B. can be administered by insufflation from an inhalation device.

For solutions, used in the production of aerosols of the invention, is the preferred concentration range of the compounds of the invention 0.1 to 100 mg / ml, more preferably 0.1 to 30 mg / ml, and most preferably 1 to 10 mg / ml. Usually are the solutions with a physiologically tolerable Buffer, such as phosphate or bicarbonate, buffered. The ordinary one pH range is 5 to 9, preferably 6.5 to 7.8 and more preferably 7.0 to 7.6. typically, sodium chloride is added to bring the osmolarity to the physiological range, preferably within 10% of the isotonic value. The formulation of such solutions for the preparation of aerosol inhalants is z. In Remington's, supra, discussed, see. also Ganderton and Johens, "Drug Delivery to the Respiratory Tract, Ellis Horwood (1987), Gonda, "Critical Review in Therapeutic Drug Carrier Systems "6, 273-313 (1990) and Raeburn et al., J. Pharmacol. Toxicol. Methods. 27, 143-159 (1992).

Solutions one Compound of the invention can be converted into aerosols by any of the known methods, which routinely Preparation of aerosol inhalation medicaments can be used. In general, such methods include pressurizing or providing means for applying a container the solution with pressure, usually with an inert carrier gas, and passing the pressurized gas through a small opening, causing droplets of the solution into the mouth and throat of the animal to which the active substance to be administered. Typically, this is a mouthpiece at the outlet of the opening attached to facilitate administration to the mouth and throat.

In an embodiment For example, devices of the present invention include solutions of Compounds of the invention produced by one of the customary means for producing of aerosols in the medication of asthma, such as metered dose inhalers, Nebulizers or ultrasonic nebulizers, connected or contained therein. Optionally, such devices may be around the opening arranged mouthpiece contain.

Further there is provided a device comprising a solution of a compound of the present invention Invention in a nasal sprayer may contain.

One dry powder containing a compound of the invention optionally with An excipient is another embodiment. This can be done by a Wirkstoffpulverinhalationsvorrichtung, the described Contains powder, be administered.

powder can with the help of all suitable powder bases, eg. Talc, lactose, Strength and the like become. Drops can with an aqueous Foundation or a non-aqueous Basis, which also includes one or more dispersants, suspending agents and solver be formulated.

each The formulations of the invention may also contain one or more preservatives or bacteriostatic agents, e.g. For example, methyl hydroxybenzoate, ethyl hydroxybenzoate, Propyl hydroxybenzoate, chlorocresol and benzalkonium chlorides. additionally can the formulations contain other active ingredients.

The Pharmaceutical formulations of the invention may be prepared by parenteral or oral administration for administered the prophylactic and / or therapeutic treatment become. The pharmaceutical compositions can be used in a variety of ways Unit dosage forms, depending from the administration method. So z. B. unit dosage forms suitable for are suitable for oral administration, powders, tablets, pills, Include capsules and dragees.

The pharmaceutical formulations can be administered intravenously. Therefore, the invention further provides formulations for intravenous administration containing a compound of the invention dissolved or suspended in a pharmaceutically acceptable carrier or diluent therefor. A variety of aqueous carriers can be used, e.g. As water, buffered water or other buffer solutions and saline. The resulting aqueous solutions may be packaged or lyophilized as they are for use, with the lyophilized preparation being combined with a sterile aqueous solution prior to administration. The sterile aqueous solution for the lyophilized product can as a kit for use with the lyophilized formulation. The compositions may contain pharmaceutically acceptable substances to aid in administration and to more closely mimic physiological conditions. Such substances may, for. PH adjusting substances such as acids, bases or buffers, tonicity adjusting agents and wetting agents. Such substances may include, but are not limited to, for example: Sodium hydroxide, hydrochloric acid, sulfuric acid, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate and triethanolamine oleate, or other means of maintaining the pH at a certain level known to those skilled in the art.

For fixed Formulations can Carrier, thinner and excipients known to those skilled in the art. Such carriers, thinner and excipients can z. Mannitol, lactose, starch, Magnesium stearate, sodium saccharin, talc, cellulose, glucose, Sucrose or other solid polyol sugar and magnesium carbonate include. For oral administration becomes a pharmaceutically acceptable formulation prepared by mixing one of the usual carriers, diluents and excipients, like those mentioned above, with 0.1 to 95% of a compound of Invention.

The preferred dosage for use in the methods of the invention is, however, in the range of 0.01 mg / kg to 100 mg / kg body weight, preferably from 0.1 mg / kg to 50 mg / kg, up to four times a day. As Whatever the dosage form, the skilled artisan recognizes that the administered Dosage of factors such as age, weight and condition of the affected patient. It is known to the practitioner how to adjust the dosage is to these and other factors too fulfill.

Although the compounds of the invention may be administered as the sole active pharmaceutical agent, the compounds may also be used in combination with one or more agents such as anti-platelet agents, anti-inflammatory agents, matrix metalloproteinase inhibitors, cancer treatment agents and anti-infective agents. So z. The compounds of the invention in combination with glycoprotein IIb / IIIa receptor antagonists for the prophylaxis and / or treatment of acute coronary ischemic syndrome ( WO 97/35615 ) or in combination with IL-1 antagonists such as p38 inhibitors (TNF-α inhibitors, IL-1 inhibitors and IL-1 receptor antagonist (IL-1Ra) for the prophylaxis and / or treatment of rheumatoid arthritis , Osteoarthritis (Arner et al., Arthritis & Rheumatism 38: 1304-1314, 1995). When administered as a combination, the therapeutic agents may be formulated as separate compositions administered at the same time or at different times. or the therapeutic agents may be administered as a single composition.

Synthesis of the compounds

Compounds of the invention can be synthesized according to one or more of the following methods. It should be noted that the general methods are shown as they relate to the preparation of compounds with unspecified stereochemistry. However, such methods are generally applicable to such compounds of specific stereochemistry, e.g. Where the stereochemistry of a group is (S) or (R). In addition, the compounds having a stereochemistry (e.g., (R)) can often be used to replace those having the opposite stereochemistry (e.g., (S)) using known methods, e.g. B. by inversion to produce. Thus, because compounds of the invention may possess one or more asymmetric carbon atoms, the compounds are capable of being in the form of both optical isomers and racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional methods, e.g. By forming diastereoisomeric salts by treatment with an optically active acid or base. Examples of suitable acids are tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Examples of suitable bases are brucine, ephedrine, strychnine and morphine. The separation of the mixture of diastereoisomers by crystallization is followed by the liberation of the optically active bases from these salts. An alternative method for separating optical isomers involves the use of a chiral chromatography column optimally selected to maximize separation of the enantiomers. Another available method involves the synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional methods such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain the enantiomerically pure compound. The optically active compounds of the invention can be obtained in the same way by using optically active starting materials or alternatively by preparing optically active synthetic intermediates either by chiral reactions, such as using a chiral reagent and a chiral catalyst, or by isolating the desired chiral synthetic intermediate isomer using the methods described above. These isomers may be in the form of a free acid, a free base, an ester or a salt.

"Outgoing group" (L) refers generally to groups easily represented by a nucleophile, such as an amine, a carbon, a thiol or an alcohol nucleophile, are displaceable. Such leaving groups are known in the art. Examples Such leaving groups include but are not limited to N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates and tosylates. preferred leaking groups are indicated herein where appropriate.

"Protective group" generally refers to to groups known in the art used to prevent selected reactive groups such as carboxy, amino, hydroxy and mercapto, undesired reactions, like nucleophilic reactions, electrophilic reactions, oxidation and Reduction (see Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, Wiley, 1991). Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to to aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted Cycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, Aralkoxycarbonyl and silyl. Examples of aralkyl include but not limited on benzyl, ortho-methylbenzyl, trityl and benzhydryl, which are optional substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino and acyl could be, and salts, such as phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9- (9-phenylfluorenyl) and phenanthrenyl. Examples of cycloalkenylalkyl or substituted Cycloalkylenylalkyl radicals preferably have 6 to 10 carbon atoms and include, but are not limited to cyclohexenylmethyl. suitable Acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, benzoyl, substituted benzoyl, Butyryl, acetyl, trifluoroacetyl, trichloroacetyl and phthaloyl. A Mixture of protecting groups can be used to the same To protect amino group, like a primary one Amino group through both an aralkyl group and an aralkoxycarbonyl group protected can be. Amino-protecting groups can also be a heterocyclic Ring with the nitrogen to which they are attached, z. For example, 1,2-bis (methylene) benzene, phthalimidyl, succinimidyl, maleimidyl and similar, and where these heterocyclic groups further adjacent aryl and May contain cycloalkyl rings. additionally can the heterocyclic groups being mono-, di- or trisubstituted, such as nitrophthalimidyl. Amino groups can also be used against unwanted reactions, such as oxidation, by the formation of an addition salt, such as hydrochloride, toluenesulphonic and trifluoroacetic acid, protected become. Many of the amino protecting groups are also protective of Carboxy, hydroxy and mercapto groups, e.g. B. aralkyl groups. Alkyl groups are also suitable groups for protecting hydroxy groups. and mercapto groups such as tert-butyl.

silyl are silicon atoms optionally containing one or more alkyl, Aryl and aralkyl groups are substituted. Suitable silyl protecting groups include, but are not limited to trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, Dimethylphenylsilyl, 1,2-bis (dimethylsilyl) benzene, 1,2-bis (dimethylsilyl) ethane and diphenylmethylsilyl. The silylation of amino groups gives Mono- or disilylamino groups. The silylation of aminoalcohol compounds may lead to an N, N, O-trisilyl derivative. The removal of the silyl function from a Silyletherfunktion is achieved in a simple manner Treatment with z. A metal hydroxide or ammonium fluoride reagent, either as a discrete reaction step or in situ during one Reaction with the alcohol group. Suitable silylating agents are z. B. trimethylsilyl chloride, tert-butyldimethylsilyl chloride, phenyldimethylsilyl chloride, Diphenylmethylsilyl chloride or its combination products with imidazole or DMF. Process for the silylation of amines and for removal Silyl protecting groups are known to those skilled in the art. Procedure for Preparation of these amine derivatives from corre sponding amino acids, amino acid amides or amino acid esters are those skilled in the field of organic chemistry, including the Amino acid / amino acid or aminoalcohol chemistry.

Protecting groups are removed under conditions that do not affect the remaining portion of the molecule. These methods are known in the art and include acid hydrolysis and hydrogenolysis. A preferred method involves the removal of a protecting group such as the removal of a benzyloxycarbonyl group by hydrogenolysis using palladium on carbon in a suitable solvent system such as an alcohol and acetic acid or mixtures thereof. A t-butoxycarbonyl protecting group may be removed using an inorganic or organic acid such as HCl or trifluoroacetic acid in a suitable solvent system such as dioxane or methylene chloride. The obtained amino salt can be easily neutralized to obtain the free amine. Carboxy protecting groups, such as methyl, ethyl, benzyl, tert-butyl and 4-methoxyphenylmethyl, can be obtained by hydrolysis and hydrogenolysis conditions are removed, which are known in the art.

links of the invention as described in the following schemes and synthetic examples, getting produced.

• 1. E + L-(Alk)_p-Q-(Alk)_q-A-G
• 2. E-OH + L-(Alk)_p-Q-(Alk)_q-A-G
• 3. E-SH + L-(Alk)_p-(Alk)_q-A-G
• 4. E-NHR₁ + L-(Alk)_p-Q-(Alk)_q-A-G
• 5. E-NHR₁ + L-C(Y)-(Alk)_p-Q-(Alk)_q-A-G
• 6. E-NHR₁ + L-C(Y)-NR₁-(Alk)_p-Q-(Alk)_q-A-G
• 7. E-NHR₁ + L-S(O)_t-(Alk)_p-Q-(Alk)_q-A-G
• 8. E-NHR₁ + L-S(O)_t-NR₁-(Alk)_p-Q-(Alk)_q-A-G
• 9. E-L + HO-(Alk)_p-Q-(Alk)_q-A-G
• 10. E-L + HS-(Alk)_p-Q-(Alk)_q-A-G
• 11. E-L + HNR₁-(Alk)_p-Q-(Alk)_q-A-G
• 12. E-C(Y)-L + HNR₁-(Alk)_p-Q-(Alk)_q-A-G
• 13. E-NR₁-C(Y)-L + HNR₁-(Alk)_p-Q-(Alk)_q-A-G
• 14. E-S(O)_t-L + HNR₁-(Alk)_p-Q-(Alk)_q-A-G
• 15. E-NR₁-S(O)_t-L + HNR₁-(Alk)_p-Q-(Alk)_q-A-G
• 16. E-B-(Alk)_p-OH + L-(Alk)_q-A-G
• 17. E-B-(Alk)_p-SH + L-(Alk)_q-A-G
• 18. E-B-(Alk)_p-NHR₁ + L-(Alk)_q-A-G
• 19. E-B-(Alk)_p-NHR₁ + L-C(X)-(Alk)_q-A-G
• 20. E-B-(Alk)_p-NHR₁ + L-C(X)-NR₁-(Alk)_q-A-G
• 21. E-B-(Alk)_p-NHR₁ + L-S(O)_t-(Alk)_q-A-G
• 22. E-B-(Alk)_p-NHR₁ + L-S(O)_t-NR₁-(Alk)_q-A-G
• 23. E-B-(Alk)_p-L + HO-(Alk)_q-A-G
• 24. E-B-(Alk)_p-L + HS-(Alk)_q-A-G
• 25. E-B-(Alk)_p-L + HNR₁-(Alk)_q-A-G
• 26. E-B-(Alk)_p-C(X)-L + HNR₁-(Alk)_q-A-G
• 27. E-B-(Alk)_p-NR₁-C(X)-L + HNR₁-(Alk)_q-A-G
• 28. E-B-(Alk)_p-S(O)_t-L + HNR₁-(Alk)_q-A-G
• 29. E-B-(Alk)_p-NR₁-S(O)-L + HNR₁-(Alk)_q-A-G
• 30. E-B-(Alk)_p-Q-(Alk)_q-L + G
• 31. E-B-(Alk)_p-Q-(Alk)_q-OH + L-G
• 32. E-B-(Alk)_p-Q-(Alk)_q-SH + L-G
• 33. E-B-(Alk)_p-Q-(Alk)_q-NHR₁ + L-G
• 34. E-B-(Alk)_p-Q-(Alk)_q-NHR₁ + L-C(X)-G
• 35. E-B-(Alk)_p-Q-(Alk)_q-NHR₁ + L-C(X)-NR₁-G
• 36. E-B-(Alk)_p-Q-(Alk)_q-NHR₁ + L-S(O)_t-G
• 37. E-B-(Alk)_p-Q-(Alk)_q-NHR₁ + L-S(O)_t-NR₁-G
• 38. E-B-(Alk)_p-Q-(Alk)_q-L + HO-C
• 39. E-B-(Alk)_p-Q-(Alk)_q-L + HS-G
• 40. E-B-(Alk)_p-Q-(Alk)_q-L + HNR₁-G
• 41. E-B-(Alk)_p-Q-(Alk)_q-C(X)-L + HNR₁-G
• 42. E-B-(Alk)_p-Q-(Alk)_q-NR₁-C(X)-L + HNR₁-G
• 43. E-B-(Alk)_p-Q-(Alk)_q-S(O)_t-L + HNR₁-G
• 44. E-B-(Alk)_p-Q-(Alk)_q-NR₁-S(O)_t-L + HNR₁-G

worin L eine austretende Gruppe, wie Chlor, Brom, Iod, Triflat, N-Hydroxysuccinimid, N-Hydroxybenzotriazol, Tosylat, Mesylat, Methoxy, Methylthiol, Phenoxy und Thiophenoxy, ist. Thioether können zu den entsprechenden Sulfinylgruppen durch Oxidation mit einem Oxidationsmittel, wie Wasserstoffperoxid und Natriumperiodat, oxidiert werden. Thioether und Sulfinylgruppen können zu den entsprechenden Sulfonylgruppen durch Oxidation mit einem Oxidationsmittel, wie Kaliumperoxymonosulfat, Kaliumpermanganat und Wasserstoffperoxid, oxidiert werden.Compounds of the invention, EB- (Alk) _p -Q- (Alk) _q -AG, can be prepared by one or more of the following coupling reactions using reagents, reaction conditions and solvents typical of such coupling reactions:

• 1. E + L- (Alk) _p -Q- (Alk) _q -AG
• 2. E-OH + L- (Alk) _p -Q- (Alk) _q -AG
• 3. E-SH + L- (Alk) _p - (Alk) _q -AG
• 4. E-NHR ₁ + L- (Alk) _p -Q- (Alk) _q -AG
• 5. E-NHR ₁ + LC (Y) - (Alk) _p -Q- (Alk) _q -AG
• 6. E-NHR ₁ + LC (Y) -NR ₁ - (Alk) _p -Q- (Alk) _q -AG
• 7. E-NHR ₁ + LS (O) _t - (Alk) _p -Q- (Alk) _q -AG
• 8. E-NHR ₁ + LS (O) _t -NR ₁ - (Alk) _p -Q- (Alk) _q -AG
• 9. EL + HO- (Alk) _p -Q- (Alk) _q -AG
• 10. EL + HS- (Alk) _p -Q- (Alk) _q -AG
• 11. EL + HNR ₁ - (Alk) _p - Q - (Alk) _q - AG
• 12. EC (Y) -L + HNR ₁ - (Alk) _p -Q- (Alk) _q -AG
• 13. E-NR ₁ -C (Y) -L + HNR ₁ - (Alk) _p -Q- (Alk) _q -AG
• 14. ES (O) _t -L + HNR ₁ - (Alk) _p -Q- (Alk) _q -AG
• 15. E-NR ₁ -S (O) _t -L + HNR ₁ - (Alk) _p -Q- (Alk) _q -AG
• 16. EB- (Alk) _p -OH + L- (Alk) _q -AG
• 17. EB- (Alk) _p -SH + L- (Alk) _q -AG
• 18. EB- (Alk) _p -NHR ₁ + L- (Alk) _q -AG
• 19. EB- (Alk) _p -NHR ₁ + LC (X) - (Alk) _q -AG
• 20. EB- (Alk) _p -NHR ₁ + LC (X) -NR ₁ - (Alk) _q -AG
• 21. EB- (Alk) _p -NHR ₁ + LS (O) _t - (Alk) _q -AG
• 22. EB- (Alk) _p -NHR ₁ + LS (O) _t -NR ₁ - (Alk) _q -AG
• 23. EB- (Alk) _p -L + HO- (Alk) _q -AG
• 24. EB- (Alk) _p -L + HS- (Alk) _q -AG
• 25. EB- (Alk) _p -L + HNR ₁ - (Alk) _q -AG
• 26. EB- (Alk) _p -C (X) -L + HNR ₁ - (Alk) _q -AG
• 27. EB- (Alk) _p -NR ₁ -C (X) -L + HNR ₁ - (Alk) _q -AG
• 28. EB- (Alk) _p -S (O) _t -L + HNR ₁ - (Alk) _q -AG
• 29. EB- (Alk) _p -NR ₁ -S (O) -L + HNR ₁ - (Alk) _q -AG
• 30. EB- (Alk) _p -Q- (Alk) _q -L + G
• 31. EB- (Alk) _p -Q- (Alk) _q -OH + LG
• 32. EB- (Alk) _p -Q- (Alk) _q -SH + LG
• 33. EB- (Alk) _p -Q- (Alk) _q -NHR ₁ + LG
• 34. EB- (Alk) _p -Q- (Alk) _q -NHR ₁ + LC (X) -G
• 35. EB- (Alk) _p -Q- (Alk) _q -NHR ₁ + LC (X) -NR ₁ -G
• 36. EB- (Alk) _p -Q- (Alk) _q -NHR ₁ + LS (O) _t -G
• 37. EB- (Alk) _p -Q- (Alk) _q -NHR ₁ + LS (O) _t -NR ₁ -G
• 38. EB- (Alk) _p -Q- (Alk) _q -L + HO-C
• 39. EB- (Alk) _p -Q- (Alk) _q -L + HS-G
• 40. EB- (Alk) _p -Q- (Alk) _q -L + HNR ₁ -G
• 41. EB- (Alk) _p -Q- (Alk) _q -C (X) -L + HNR ₁ -G
• 42. EB- (Alk) _p -Q- (Alk) _q -NR ₁ -C (X) -L + HNR ₁ -G
• 43. EB- (Alk) _p -Q- (Alk) _q -S (O) _t -L + HNR ₁ -G
• 44. EB- (Alk) _p -Q- (Alk) _q -NR ₁ -S (O) _t -L + HNR ₁ -G

wherein L is an leaving group such as chlorine, bromine, iodine, triflate, N-hydroxysuccinimide, N-hydroxybenzotriazole, tosylate, mesylate, methoxy, methylthiol, phenoxy and thiophenoxy. Thioethers can be oxidized to the corresponding sulfinyl groups by oxidation with an oxidizing agent such as hydrogen peroxide and sodium periodate. Thioethers and sulfinyl groups can be oxidized to the corresponding sulfonyl groups by oxidation with an oxidizing agent such as potassium peroxymonosulfate, potassium permanganate and hydrogen peroxide.

The preparation of amidine groups, such as when B is a radical -C (Y) -N (R ₁ ) - or -N (R ₁ ) -C (Y) -, is known to the skilled worker (see Baati et al., Synthesis 1999: 927-929; Dunn, Comer. Org. Funct., Group Transform. 5: 741-82 and 1161-308, 1995; and Gautier et al., Chem. Amidines Imidates, Patai (ed.), Wiley (1975). , Pages 283-348). Guanidine groups, such as when B is a radical -N (R ₁ ) -C (Y) -N (R ₁ ) - may be prepared from urea groups (e.g., by reaction with POCl ₃ and a substituted amine in an organic solvent such as toluene) from thiourea groups (e.g., by reaction with a substituted amine in the presence of CuSO ₄ , SiO ₂ and a base such as triethylamine in an organic solvent such as tetrahydrofura (Tet. Lett. 36: 2841-2844 , 1995) or sodium periodate in the presence of base in dimethylformamide and water (Synlett 1997: 1053-1054)), from substituted cyanamide groups -N (R) -CN (eg, by reaction with a substituted amine), from iminoesteramine groups R ' OC (NR) -N (R) - (for example by reaction with a substituted amine) or from iminothioesteramine groups, R'S-C (NR) -N (R) - (by reaction with a substituted amine (Synth. 29: 1757-1766, 1999).

Schema 2

Schemes 1 and 2 illustrate the preparation of compounds of the invention wherein G is a benzazepine-type ring system. Compounds (21) and (22) wherein A ₁ - is EB- (Alk) _p -Q- (Alk) _q -A- or an intermediate (such as MB- (Alk) _p -Q- (Alk) _q -A-, M- (Alk) _p -Q- (Alk) _q -A-, MQ- (Alk) _q -A-, M- (Alk) _q -A- and MA-, wherein M is a reactive component , such as an electrophile, nucleophile, or leaving group or group that can be converted to an electrophile, nucleophile, or leaving group that can be easily converted into the EB (Alk) _p -Q (Alk) radical. _q -A- can be prepared from the corresponding amines (23) and (25), respectively, by alkylation, acylation and sulfonylation with A _{1 -L} , where L is an leaving group such as a halide, a tosylate, a mesylate and a carboxylic acid activating group (such as N-hydroxysuccinimide, carbodiimide (Tetrahedron 55: 6813-6830, 1999), BOP (J. Org. Chem 63: 9678-9683, 1998)) Alternatively, compounds (21) and (22) are prepared by (a) nucleophilic displacement by A. ₁ -NH _{2 of} the leaving groups (L) on the compounds (24) or (26), (b) a reductive amination of the compounds (24) or (26), wherein LX ₂ - and LX ₃ - a ketone or an aldehyde, using A ₁ -NH ₂ and a reducing agent (such as sodium cyanoborohydride and PtO ₂ / H ₂ ) or (c) a mixture of both (a) and (b). The reaction of A ₁ -NH ₂ with LX ₂ - and LX ₃ - can be carried out simultaneously (one-pot reaction) or in successive stepwise reactions. Scheme 1

Scheme 2

wie mit organometallischen Verbindungen (wie (R₄)₂CuLi oder R₁₀-Li), oder alternativ durch Oxidieren der Hydroxygruppe zu einer Carbonsäure, Umsetzen der Säure mit einem Nucleophil von R₄ bzw. R₁₀, wie R₄-Li oder R₁₀-MgBr, und anschließendes Reduzieren des erhaltenen Ketons zu der Hydroxygruppe, wie mit Natriumcyanborhydrid. Der Alkohol (28a/b) kann in die Sulfonylverbindung (29a/b) umgewandelt werden durch Umwandeln der Hydroxygruppe in eine austretende Gruppe (wie ein Halogenid, Tosylat, Mesylat oder Triflat), nucleophile Verdrängung der austretenden Gruppe mit einem Thiolsalz (wie Natriumsulfid) und anschließende Umwandlung des erhaltenen Thiols in ein Sulfonylhalogenid (wie Cl₂/H₂O-Oxidation). Die Alkohole (27a/b) bzw. (28a/b) können in die Cyanverbindungen (30a/b) bzw. (31a/b) durch Umwandeln der Hydroxygruppe in eine austretende Gruppe, wie zuvor, ge folgt von einer nucleophilen Verdrängung der austretenden Gruppe mit einem Cyanidsalz (wie Natriumcyanid) umgewandelt werden. Die Cyanverbindung (31a/b) kann aus einer Cyanverbindung (30a/b) durch eine nucleophile Verdrängungsreaktion mit R₄-L bzw. R₁₀-L in Gegenwart von Base hergestellt werden. Die Cyanverbindung (31a/b) kann zu dem Amin (32a/b) reduziert werden, wie mit BH₃-Me₂S. Die Cyanverbindungen (30a/b) bzw. (31a/b) können zu einer Carbonsäure hydrolysiert werden, die dann verestert (P₂) werden kann zur Bildung von Estern (33a/b) bzw. (34a/b), oder die Säure (34a/b) kann in einen aktiven Ester (35a/b) umgewandelt werden. Wie in dem Fall der Cyanverbindung (30a/b) kann die Esterverbindung (33a/b) ein nucleophile Verdrängungsreaktion mit R₄-L bzw. R₁₀-L in Gegenwart von Base (wie Natriumhydrid oder Ähnliches) eingehen zum Herstellen des Esters (34a/b). Die Ester (33a/b) und (34a/b) können eine Kondensationsreaktion mit R_6,7-C(O)-L, worin R_6,7-Reste R₆- oder R₇-, wie hierin definiert, bedeutet, in Gegenwart von Base, wie Natriumhydrid, eingehen, gefolgt von einer Hydrolyse und Decarboxylierung zum Erhalt von Ketonen (36a/b) bzw. (37a/b). Das Keton (36a/b) kann auch eine nucleophile Verdrängung von R₄-L bzw. R₁₀-L in Gegenwart von Base eingehen zum Erhalt des Ketons (37a/b). Das Keton (37a/b) kann eine reduktive Aminierung mit A₁-NH₂ oder P_N-NH₂ (worin P_N eine Stickstoffschutzgruppe, wie Benzyl oder BOC, ist) eingehen oder kann alternativ reduziert werden, und der entsprechende Alkohol kann in eine austretende Gruppe umgewandelt werden zum Erhalt der Verbindung (38a/b). Die Auswahl, welche Kombination von Komponenten für X₂ und X₃ bei der Herstellung der Verbindung (21) zu verwenden ist, liegt im Können des Fachmanns.Schemes 3 and 4 illustrate the preparation of synthetic intermediates useful in the preparation of compounds (23) and (24). Scheme 3 relates to the preparation of the X ₂ portion of the compounds, and Scheme 4 relates to the X ₃ portion of the compounds. The compound (28a / b) can be prepared from (27a / b) by oxidizing the hydroxy group to an aldehyde, such as by a Swern oxidation, and reacting the aldehyde with a nucleophile of R ₄ and R ₁₀ , Scheme 3, respectively

as with organometallic compounds (such as (R ₄ ) ₂ CuLi or R ₁₀ -Li), or alternatively by oxidizing the hydroxy group to a carboxylic acid, reacting the acid with a nucleophile of R ₄ and R ₁₀ , such as R ₄ -Li or R ₁₀ -MgBr, and then reducing the obtained ketone to the hydroxy group, as with sodium cyanogen anborhydrid. The alcohol (28a / b) can be converted to the sulfonyl compound (29a / b) by converting the hydroxy group to an leaving group (such as a halide, tosylate, mesylate or triflate), nucleophilic displacement of the leaving group with a thiol salt (such as sodium sulfide). and subsequent conversion of the resulting thiol to a sulfonyl halide (such as Cl ₂ / H ₂ O oxidation). The alcohols (27a / b) or (28a / b) can be converted into the cyano compounds (30a / b) or (31a / b) by converting the hydroxy group into an leaving group, as before, followed by nucleophilic displacement of the leaving one Group with a cyanide salt (such as sodium cyanide) to be converted. The cyano compound (31a / b) can be prepared from a cyano compound (30a / b) by a nucleophilic displacement reaction with R ₄ -L or R ₁₀ -L in the presence of base. The cyano compound (31a / b) can be reduced to the amine (32a / b) as with BH ₃ -Me ₂ S. The cyano compounds (30a / b) and (31a / b), respectively, can be hydrolyzed to a carboxylic acid then esterified (P ₂ ) can be used to form esters (33a / b) and (34a / b), respectively, or the acid (34a / b) can be converted to an active ester (35a / b). As in the case of the cyano compound (30a / b), the ester compound (33a / b) may undergo nucleophilic displacement reaction with R ₄ -L and R ₁₀ -L in the presence of base (such as sodium hydride or the like) to produce the ester (34a / b). The esters (33a / b) and (34a / b) can undergo a condensation reaction with R _6,7 -C (O) -L, where R _{6,7 is} -R ₆ - or R ₇ - as defined herein, in the presence of base, such as sodium hydride, followed by hydrolysis and decarboxylation to give ketones (36a / b) and (37a / b, respectively). The ketone (36a / b) may also undergo nucleophilic displacement of R ₄ -L or R ₁₀ -L in the presence of base to yield the ketone (37a / b). The ketone (37a / b) may undergo reductive amination with A ₁ -NH ₂ or P _N -NH ₂ (where P _{N is} a nitrogen protecting group such as benzyl or BOC) or may alternatively be reduced and the corresponding alcohol may be present in a leaving group is converted to give the compound (38a / b). The choice of which combination of components to use for X ₂ and X ₃ in the preparation of compound (21) is within the skill of the art.

Scheme 4

Schemes 5, 6 and 7 illustrate the preparation of compounds (25) and (26). Schemes 5 and 6 relate to the preparation of the X ₂ portion of the compounds, and Scheme 7 concerns the X ₃ portion of the compounds. The compound (40) may be selected from the aldehyde (39) as described above for the compound (28) ben, be prepared. In the scheme (5), the condensation of P ₂ O ₂ CCH ₂ R ₁₂ (or alternatively the corresponding Wittig reagent (Chem. Rev. 89: 863-927, 1989) or the Horner-Wadsworth-Emmons condensation (Tet Lett., 24: 4405-4408, 1983)) with a compound (39) in Scheme 5

Presence of base, such as sodium hydride or the like, the unsaturated ester (41) which can undergo a nucleophilic Michael-type reaction to introduce the radical R ₄ , as with (R ₄ ) ₂ Cu, to obtain the ester (42 ). Alternatively, condensation of P ₂ O ₂ CCH ₂ R ₁₂ with compound (40) in the presence of base, such as sodium hydride, can yield the ester (42) directly. The ester (42) can be converted to an activated ester (43) which can be reacted with A ₁ -NH ₂ or P _N -NH ₂ . Alternatively, the ester (42) may undergo a condensation reaction with R _6,7 -C (O) -L, followed by hydrolysis and decarboxylation to yield the ketone (44). The ketone (44) may undergo reactive amination with A ₁ -NH ₂ or P _N -NH ₂ , or alternatively may be reduced, and the corresponding alcohol may be converted to an leaving group to give the compound (45).

Scheme 6

In Scheme 6, the esters (33a) and (34a) can undergo a condensation reaction with R ₁₂ -C (O) -L in the presence of base, such as sodium hydride, followed by hydrolysis and decarboxylation to yield the ketones (46) and (34a), respectively (47). The ketone (46) may also undergo nucleophilic displacement of R ₄ -L in the presence of base to yield the ketone (47). Reduction of the ketone (47) and conversion of the resulting alcohol to an leaving group (such as a halide, tosylate, mesylate, triflate) as described above can yield the compound (48). Nucleophilic displacement of the leaving group of compound (48) with a thiol salt (such as sodium sulfide) and subsequent conversion of the resulting thiol to a sulfonyl halide (such as Cl ₂ / H ₂ O oxidation) can yield compound (49).

Scheme 7

In Scheme 7, the ketone (50) can be prepared from the corresponding carboxylic acid by reacting the acid with a nucleophile of R _6.7 , such as R _6,7 -Li or R _6,7 -MgBr, or alternatively, by acylating the aromatic Rings with R _6,7 -C (O) -L in the presence of a Friedel-Crafts catalyst such as AlCl ₃ , or alternatively by a nucleophilic reaction of R _6,7 -C (O) -L or R _6,7 - CO ₂ H with the corresponding organometallic salt of the aromatic ring. The ketone (50) may undergo reductive amination with A ₁ -NH ₂ or P _N -NH ₂ , or alternatively may be reduced, and the corresponding alcohol may be converted to a leaving group to give the compound (51). The sulfonyl compound (53) can be prepared from the corresponding thiol (52) (as by a Cl ₂ / H ₂ O oxidation) which can be prepared by nucleophilic displacement of the corresponding halide with a thiol salt (such as sodium sulfide).

Scheme 8

Alternatively, compounds (21) and (22) can be prepared by a Heck cyclization (Trans. Met. Org. Synth. 1: 208-240, 1998) as shown in Schemes 8 and 9. Unsaturated esters (54) and (55) wherein L is an leaving group such as a halide or triflate can be cyclized in the presence of Pd (PPh ₃ ) ₄ to give compounds (56) and (57), respectively. The double bond of compounds (56) and (57) can be reduced (as by hydrogenation in the presence of Pd / C catalyst, magnesium in methanol or the like), and the ester groups can be prepared using methods described above and standard methods known to those skilled in the art are easily converted into groups represented by the radical R ₄ . The unsaturated esters (54) and (55) can be prepared by nucleophilic displacement of the leaving group L of the compounds (58) and (60) with amino compounds (59) and (61), respectively, which are commercially available or in a simple manner can be prepared from commercially available starting materials. Instead of the nitrogen protecting group P _N - A ₁ - or a hydrogen atom can be used.

Scheme 9

alternative can the compounds (54) and (55) by radical chain reaction under Use of a suitable initiator, such as AIBN (Tet. 2829-2832, 1991) to esters (56) and (57), respectively, in which the double bond is saturated is.

The Schematics 10 and 11 explain the preparation of compounds of the invention wherein G is an imidazolo-fused or benzazepine-type triazolo-fused ring system. In the schemata (10) and (11) may be the imidazolo-fused or triazolo-fused ring system Benzazepine type (80) and (83) substituted imidazoles and Triazoles (which are commercially available are or simply from commercially available starting materials by alkylation of the imidazole or triazole nitrogen be prepared with alkylating agents (79) and (81). The cyclization may be by conversion of the hydroxy group of the alkylating agent be effected in a leaving group which is a nucleophilic displacement after metalation of the bromo group (alternatively the chlorine or iodine group) of imidazole or triazole. The person skilled in the art recognizes that other known methods, conditions and methods are used can, to effect the cyclization. The alkylating agents (79) and (81) according to the above be prepared described methods.

Scheme 10

Scheme 11

The reactions described above can be carried out in all solvents, in which the reactants are mutually soluble, including e.g. B. tetrahydrofuran, benzene, toluene, chloroform, dichloromethane, N, N-dimethylformamide, Ethyl ether, dioxane, water or acetonitrile. Usually the reaction is added a temperature between -80 ° C and 150 ° C, preferably however, carried out at room temperature. In certain cases, like in the examples presented herein, the temperature the reaction, however, 360 ° C. reach or exceed.

The Product and intermediates can be isolated or purified using one or more standard purification techniques, including z. B. one or more techniques from the group of a simple Solvent evaporation, Recrystallization, distillatioin, sublimation, filtration, chromatography, including thin layer chromatography, HPLC (e.g., reverse phase HPLC using, for example, dilute trifluoroacetic acid in water, Acetonitrile or methanol mixtures as eluent), column chromatography, Flash chromatography, radial chromatography and rubbing.

at the preparation of the compounds of the invention is understood by the person skilled in the art, that it may be necessary to use different reactive functionalities Protect parent compounds or intermediates or while blocking a desired one Reaction to other parts of the molecule is performed. After the desired Responses fully constantly are or to everyone desired Normally, such protecting groups are removed by, e.g. B. hydrolytic or hydrogenolytic process. Such protection and Deprotection steps are common in organic chemistry. Of the Professional becomes for the doctrine of protecting groups used in the preparation of the compounds of the present invention, to "Protective Groups in Organic Chemistry", McOmie, eds. Plenum Press, New York, NY and "Protective Groups in Organic Synthesis", Greene, eds., John Wiley & Sons, New York, NY (1981).

alternative Process in addition to the above for the preparation of the compounds The methods described in the invention will be apparent to those skilled in the art, and the said general methods must not be considered the invention restrictive be interpreted. To the invention including the method for manufacturing more fully understand the compounds of the invention the following non-limiting Examples presented. The reader recognizes that starting materials, which are not described herein, are either commercially available or from commercially available Compounds prepared by methods generally known in the art can be.

Unless otherwise stated, all materials were obtained from industrial suppliers and used without further purification. Anhydrous solvents such as dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (CH ₂ Cl ₂ ), toluene and dioxane were obtained from Aldrich Chemical Company in containment bottles. All reactions involving air- or moisture-sensitive compounds were carried out under an N ₂ atmosphere. Flash chromatography was performed using ICB Biomedicals (SiliTech 32-63D 60A). Thin layer chromatography (TLC) was performed on Analtech or Whatman silica gel TLC plates (250 μm). Preparative TLC was performed on Whatman silica gel TLC plates (2000 μm). ¹ H NMR spectra were determined with superconducting FT-NMR spectrometers operating at 400 and 500 MHz. Chemical shifts are expressed in ppm downfield from internal tetramethylsilane. Significant ¹ H NMR data are given in the following order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet, m, multiplet, quin, quintet), number of protons and coupling constants in Hz. Elemental analyzes were performed by Atlantic Microlab, Inc., Norcross, GA. Melting points were determined with a capillary melting point Buchi 535 and are uncorrected. Low resolution (MS) mass spectra were determined on a Perkin Elmer SCIEX API 165 mass spectrometer using APCI or ES ionization modes (positive or negative). High resolution mass spectra (HRMS) were performed by Mass Consortium, San Diego, CA using FAB ionization.

Example 1 (reference)

Preparation of methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate hydrochloride

Step A: 3 - (((2-Bromophenol) methyl) amino) propan-1-ol

To a stirred solution of 2-bromobenzaldehyde in dichloroethane (0.4 M) at RT under nitrogen was added 3-aminopropanol (1.5 eq.), Sodium triacetoxyborohydride (2 eq.) And acetic acid (4 eq.). After 5 hours, the reaction was quenched thoroughly with 2M sodium carbonate and extracted with methylene chloride. The organic phase was extracted with 1N hydrochloric acid. The aqueous phase was neutralized with 1N sodium hydroxide and extracted with methylene chloride. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product.
EI-MS m / z 245 (M + H) ⁺ .

Step B: (tert-butoxy) -N - ((2-bromophenyl) methyl) -N- (3-hydroxypropyl) carboxamide

To a stirred solution of 3 - (((2-bromophenyl) methyl) amino) propan-1-ol in methylene chloride (0.1 M) was added di-tert-butyl dicarbonate (1.1 eq.). After 1 hour, the solvent was removed by rotary evaporation and the residue was partitioned between ether and 1N HCl. The ether portion was dried over sodium sulfate, filtered and dried under reduced pressure to give the product. EI-MS m / z 344 (M + H) ⁺ .

Step C: Methyl (2E) -5- (N- (tert-butoxycarbonyl) -N - ((2-bromophenyl) methylamino) pent-2-enoate

To a stirred solution of dimethyl sulfoxide (3.8 eq.) In methylene chloride (0.1 M) at -78 ° C was added oxalyl chloride (1.8 eq.). After 10 minutes, (tert-butoxy) -N - ((2-bromophenyl) methyl) -N- (3-hydroxypropyl) carboxamide (1 eq.) Was added. After stirring for 30 minutes, diisopropylethylamine (4 eq.) Was added and the reaction was allowed to warm to rt. After 30 minutes, methyl (triphenylphosphoranylidene) acetate (1.2 eq.) Was added and stirring was continued for 18 hours. The mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product. EI-MS m / z 398 (M + H) ⁺ .

Step D: Methyl 2- (2- (tert-butoxycarbonyl) -1H, 3H, 4H-benzo [e] azaperhydroepin-5-ylidene) acetate

To a stirred solution of methyl (2E) -5- (N- (tert-butoxycarbonyl) -N - ((2-bromophenyl) methyl) amino) pent-2-enoate in toluene (0.1M) was added triethylamine ( 1.5 eq.) And tetrakis (triphenylphosphine) palladium (0.05 eq.). The reaction was refluxed under nitrogen for 48 hours and cooled to RT. The solvent was removed by rotary evaporation and the product was purified by flash chromatography (10% EtOAc / hexane). EI-MS m / z 326 (MH) ⁺ .

Step E: Methyl 2- (2- (tert-butoxycarbonyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

To a stirred solution of methyl 2- (2- (tert-butoxycarbonyl) -1H, 3H, 4H-benzo [e] azaperhydroepin-5-ylidene) acetate in methanol (0.1M) was added magnesium turnings (10 eq.). added and the mixture was heated under reflux for 18 hours. The mixture was filtered through celite and concentrated by rotary evaporation. The product was purified by flash chromatography (25% EtOAc / hexane). EI-MS m / z (M + H) ⁺ .

Step F: Methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate hydrochloride

Methyl 2- (2- (tert-butoxycarbonyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate was dissolved in 4 M HCl in dioxane (0.2 M). After 18 hours, the solvent was removed under reduced pressure followed by trituration with ether to give the product. EI-MS m / z 220 (M + H) ⁺ .

Example 2

Preparation of 2- (2- (N- (3- (2-pyridylamino) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

Step A: 2- (N- (3-Aminoprop-1-yl) amino) pyridine

To a stirred solution of 2-fluoropyridine in pyridine (0.5 M) was added 1,3-propanediamine (5 eq.) And the solution was heated at reflux overnight. The solution was then concentrated under reduced pressure and the residue was partitioned between ethyl acetate and 10% sodium carbonate. The phases were separated and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed (silica, 10: 1: 1 EtOH / NH ₄ OH / H ₂ O) to give a viscous pale yellow oil.
EI-MS m / z 152 (M + H) ⁺ .

Step B: Methyl 2- (2- (N- (3- (2-pyridylamino) prop-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate

Methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate hydrochloride was dissolved in methylene chloride and washed with 1N NaOH. The organic layer was separated, dried over sodium sulfate and concentrated by rotary evaporation. The residue was stirred under nitrogen with 20% phosgene in toluene (0.1 M) for 10 minutes. After concentration by rotary evaporation, the residue was dissolved in THF (0.1 M), followed by the addition of diisopropylethylamine (1.5 eq) and 2- (N- (3-aminoprop-1-yl) amino) pyridine ( 1.2 eq.). The reaction mixture was stirred under nitrogen for 18 hours, followed by concentration by rotary evaporation and the product was purified by flash chromatography purified (5% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 397 (M + H) ⁺ .

Step C: 2- (2- (N- (3- (2-Pyridylamino) prop-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

To a stirred solution of methyl 2- (2- (N- (3- (2-pyridylamino) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate in methanol ( 0.1 M) was added 1 N NaOH (3 eq.). After 18 hours, the reaction mixture was neutralized with 10% HCl, concentrated by rotary evaporation, and purified by recrystallization from 2% MeOH / CH ₂ Cl ₂ . EI-MS m / z 383 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.90 (d, J = 4.4 Hz, 1H), 7.31 (m, 2H), 7.25 (m, 2H), 7, 06 (m, 1H), 6.48 (m, 4H), 4.48 (q, J = 30Hz, 2H), 3.53 (dd, J = 6Hz, 2H), 3.39 (d, J = 7Hz, 1H), 3.30 (m, 1H), 3.12 (m, 2H), 3.00 (m, 2H), 2.45 (d, J = 5.5Hz, 2H) , 1.83 (m, 1H), 1.60 (m, 2H), 1.49 (m, 1H).

Example 3

2- (2- (N- (4- (2-pyridylamino) butyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

2- (2- (N- (4- (2-Pyridylamino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid was prepared from 2- (N - (4-Aminobut-1-yl) amino) pyridine and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate prepared according to the method of Example 2.
EI-MS m / z 397 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.91 (d, J = 4 Hz, 1H), 7.43 (m, 2H), 7.19 (m, 3H), 6.48 ( m, 3H), 6.32 (t, J = 10Hz, 1H), 4.48 (s, 2H), 3.52 (m, 2H), 3.41 (m, 2H), 3.17 ( d, J = 5.4 Hz, 2H), 2.96 (m, 2H), 2.68 (m, 2H), 1.81 (m, 1H), 1.48 (m, 2H), 1, 41 (m, 2H).

Example 4

2- (2- (N- (5- (2-pyridylamino) pent-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

2- (2- (N- (5- (2-Pyridylamino) pent-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid was prepared from 2- (N - (5-aminopent-1-yl) amino) pyridine and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-S-yl) acetate prepared according to the method of Example 2. EI-MS m / z 411 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.89 (d, J = 1.4 Hz, 1H), 7.28 (m, 2H), 7.13-7.10 (m, 4H ), 6.37 (m, 2H), 6.25 (t, J = 5.3 Hz, 1H), 4.38 (s, 2H), 3.41 (m, 2H), 3.34 (m , 2H), 3.25 (m, 2H), 3.09 (t, J = 17Hz, 2H), 2.61 (m, 2H), 1.75 (m, 1H), 1.40 (m, 2H), 1.29 (m, 2H), 1.03 (m, 2H).

Example 5

2- (2- (N-methyl-N- (4- (2-pyridylamino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

2- (2-N-Methyl-N- (4- (2-pyridylamino) butyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid was prepared from 2- (N- (4- (Methylamino) but-1-yl) amino) pyridine and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate prepared according to the method of Example 2. EI-MS m / z 411 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 8.08 (d, J = 5 Hz, 1H), 7.50 (m, 1H), 7.41-7.23 (m, 5H), 6.60 (m, 2H), 4.50 (q, J = 34 Hz, 2H), 3.68 (m, 2H), 3.35 (m, 3H), 3.13 (m, 1H), 2.87 (d, J = 7Hz, 2H), 2.69 (m, 5H), 2.11 (m, 1H), 1.88 (m, 1H), 1.69 (m, 1H), 1.41 (m, 2H).

Example 6

2- (2- (N- (4- (2-pyridylamino) -trans-cyclohexyl) carbamoyl) -1H, 3H, 4H,5H-benzo [e] azepin-5-yl) acetic acid

2- (2- (N- (4- (2-pyridylamino) -trans-cyclohexyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid was prepared from 2- (N- (trans-4-aminocyclohexyl) amino) pyridine and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate prepared according to the method of Example 2. EI-MS m / z 423 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d4-CD ₃ OD): δ 7.70 (d, J = 4.6 Hz, 1H), 7.50 (m, 1H), 7.20 to 6.85 (m , 6H), 6.42 (m, 2H), 4.45 (q, J = 9Hz, 2H), 4.38 (m, 1H), 3.52 (m, 1H), 3.41 (m , 4H), 2.61 (m, 3H), 1.91 (m, 3H), 1.76 (m, 2H), 1.50 (m, 1H), 1.39-1.11 (m, 3H).

Example 7

2- (2 - (((4- (2-pyridylamino) methyl) piperid-1-yl) carbonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

2- (2 - (((4- (2-Pyridylamino) methyl) piperid-1-yl) carbonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid was prepared from 2- N- (piperid-4-ylmethyl) amino) pyridine and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate were prepared according to the method of Example 2. EI-MS m / z 423 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 8.02 (d, J = 4.5 Hz, 1H), 7.43 (t, J = 16 Hz, 1H), 7.29 (d, J = 7Hz, 1H), 7.20-6.96 (m, 3H), 6.74 (d, J = 12Hz, 1H), 6.50 (t, J = 8Hz, 1H), 4 , 42 (q, J = 24 Hz, 2H), 4.20 d, J = 12 Hz, 2H), 3.70-3.20 (m, 4H), 2.85 (m, 2H), 2.62 (t, J = 24Hz, 2H), 2.31 (d, J = 7Hz, 2H), 1.79 (m, 1H), 1.59 (m , 2H), 1.47 (m, 1H), 0.99 (q, J = 11 Hz, 2H).

Example 8

2- (2- (N- (3- (2-pyridylamino) methylphenyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

2- (2- (N- (3- (3-Pyridylamino) methylphenyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid was prepared from 2- (N - ((3 -Aminophenyl) methyl) amino) pyridine and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate prepared according to the method of Example 2. EI-MS m / z 431 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 8.02 (s, 1H), 7.84 (m, 1H), 7.32 (s, 1H), 7.00 (m, 4H), 6.83 (m, 1H), 6.78 (d, J = 7.5Hz, 1H), 6.30 (m, 2H), 4.51 (q, J = 8.5Hz, 2H), 4.26 (s, 2H), 3.56 (s, 2H), 3.38 (m, 1H), 2.60 (m, 2H), 1.80 (m, 1H), 1.48 (m , 1H).

Example 9

2- (2- (N- (4 - ((6-methyl-2-pyridyl) amino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

2- (2- (N- (4 - ((6-methyl-2-pyridyl) amino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid was prepared from 6-methyl-2- (N- (4-aminobut-1-yl) amino) pyridine and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl). acetate according to the method of Example 2. EI-MS m / z 411 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.52 (m, 1H), 7.32 (d, J = 7 Hz, 1H), 7.14 (m, 4H), 6.41 ( m, 2H), 6.32 (m, 1H), 4.48 (s, 2H), 3.59 (s, 2H), 3.41 (m, 2H), 3.20 (m, 2H), 2.99 (m, 2H), 2.70 (q, J = 17Hz, 2H), 2.34 (s, 3H), 1.82 (m, 1H), 1.47 (m, 4H).

Example 10

2- (2- (N- (4- (pyrimidin-2-ylamino) but-1-yl) carbamoyl) -1H, 3H,4H, 5H-benzo [e] azapin-5-yl) acetic acid

2- (2- (N- (4- (pyrimidin-2-ylamino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid was prepared from 6- Methyl 2- (N- (4-aminobut-1-yl) amino) pyrimidine and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaper hydroquinine-S-yl) acetate was prepared according to the method of Example 2. EI-MS m / z 398 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 8.07 (d, J = 4.4 Hz, 1H), 7.25-6.82 (m, 5H), 6.36 (t, J = 10Hz, 1H), 6.12 (m, 1H), 4.26 (s, 2H), 3.31 (s, 2H), 3.21 (m, 2H), 3.00 (t, J = 6Hz, 2H), 2.78 (m, 2H), 2.50 (q, J = 48Hz, 2H), 1.62 (m, 1H), 1.22 (m, 4H).

Example 11

2- (2- (N- (3- (6-amino-2-pyridyl) prop-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid hydrochloride

2- (2- (N- (3- (6-amino-2-pyridyl) prop-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid hydrochloride was prepared from 6-amino-2- (3-aminoprop-1-yl) pyridine and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate according to the method of Example 2 produced. EI-MS m / z 383 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d4-CD ₃ OD): δ 7.90 (t, J = 8.7 Hz, 1H), 7.42 (d, J = 7.1 Hz, 1H), 7, 30 (m, 3H), 6.91 (d, J = 8.1 Hz, 3H), 6.32 (d, J = 7.2 Hz, 1H), 4.69 (q, J = 30 Hz, 2H), 3.80 (m, 1H), 3.69 (m, 2H), 3.37 (t, J = 12 Hz, 2H), 2.91 (m, 2H), 2.72 (t, J = 14Hz, 2H), 2.17 (m, 1H), 1.92 (t, J = 14Hz, 2H), 1.70 (m, 1H).

Example 12 (reference)

2- (2- (N- (6- (tert-butoxycarbonylamino) -2-pyridyl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl (3-) acetic acid

2- (2- (N- (6- (tert-butoxy) carbonylamino) -2-pyridyl) propyl) carbamoyl (3-) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid was prepared from 6- (tert-butoxycarbonylamino) -2- (3-aminoprop-1-yl) pyridine and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate according to prepared by the method of Example 2. EI-MS m / z 483 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d4-CD ₃ OD): δ 7.63 (m, 2H), 7.30 (d, J = 7 Hz, 1H), 7.27 to 7.12 (m, 4H ), 6.82 (d, J = 7Hz, 1H), 4.55 (q, J = 53Hz, 2H), 3.68 (m, 1H), 3.56 (m, 2H), 3, 20 (t, J = 16Hz, 2H), 2.76 (m, 2H), 2.63t, J = 15Hz, 2H), 2.04 (m, 1H), 1.86 (t, J = 15 Hz, 2H), 1.59 (s 9H), 1.32 (m, 1H).

Example 13

2- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) prop-1-yl) carbamoyl) -1H, 3H, 4H,5H -benzo [e] azapin-5-yl) acetic acid

2- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) prop-1-yl) carbamoyl) -1H, 3H, 4H, 5H benzo [e] azapin-5-yl) acetic acid was prepared from 3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) prop-1-ylamine and methyl 2- 1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate prepared according to the method of Example 2. 3- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-yl) prop-1-ylamine was prepared according to Duggan, ME. WO 98/18460 produced. EI-MS m / z 423 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.30-6.98 (m, 5H), 6.30 (m, 1H), 6.20 (d, J = 7 Hz, 1H), 4.41 (q, J = 36 Hz, 2H), 3.60 (m, 1H), 3.40 (m, 2H), 3.24 (t, J = 11 Hz, 2H), 2.94 ( m, 2H), 2.61 (t, J = 13Hz, 2H), 2.36 (t, J = 15Hz, 2H), 2.28 (d, J = 7Hz, 2H), 1.80 (m, 3H), 1.64 (t, J = 8Hz, 2H), 1.40 (m, 1H).

Example 14

Preparation of 2- (2 - (((4- (2-pyridylamino) but-1-yl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

Step A: 2-Hydroxyphenyl ((4- (2-pyridylamino) butyl) amino) sulfonate

To a stirred solution of N- (2-pyridyl) -1,4-butanediamine and triethylamine (1.1 eq.) In dimethylformamide (0.15 M) at 0 ° C was catechol sulfate (1.1 eq.) In methylene chloride (0.15 M) was added. After 3 hours, the reaction mixture was poured into water and extracted with diethyl ether. The ether extract was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the product. EI-MS m / z 338 (M + H) ⁺ .

Step B: Methyl 2 - (((4- (2-pyridylamino) but-1-yl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate

2-hydroxyphenyl ((4- (2-pyridylamino) but-1-yl) amino) sulfonate (1 eq.) And methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5 yl) acetate (1 eq.) was dissolved in dioxane (0.1 M) and refluxed under nitrogen for 5 h. After removal of the solvent by rotary evaporation and flash chromatography (5% MeOH in CH ₂ Cl ₂ ) the product was obtained. EI-MS m / z 447 (M + H) ⁺ .

Step C: 2- (2 - (((4- (2-Pyridylamino) but-1-yl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

Methyl 2- (2 - (((4- (2-pyridylamino) but-1-yl) -amino) -sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate was prepared according to Method of Example 2 saponified. EI-MS m / z 433 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.80 (d, J = 4 Hz, 1H), 7.19 (t, J = 14 Hz, 1H), 7.13-6.92 ( m, 5H), 6.38 (m, 1H), 6.30 (m, 2H), 4.25 (q, J = 32Hz, 2H), 3.42 (m, 1H), 3.36 ( m, 1H), 3.04 (m, 2H), 2.46 (m, 2H), 2.28 (m, 2H), 1.75 (m, 1H), 1.41 (m, 1H), 1.28 (m, 4H).

Example 15

2- (2 - (((3- (2-pyridylamino) prop-1-yl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

2- (2 - (((3- (2-pyridylamino) propyl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid was prepared from 2-hydroxyphenyl (3- (2-pyridylamino) prop-1-yl) amino) sulfonate and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate prepared according to the method of Example 14. EI-MS m / z 419 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.95 (d, J = 4.3 Hz, 1H), 7.35 (t, J = 14 Hz, 1H), 7.26-7, 06 (m, 5H), 6.57 (m, 1H), 6.41 (t, J = 13Hz, 2H), 4.38 (q, J = 41Hz, 2H), 3.58 (m, 3H), 3.19 (t, J = 3.5Hz, 2H), 2.70 (t, J = 3Hz, 2H), 2.38 (d, J = 7Hz, 2H), 1.88 (m, 1H), 1.60 (m, 2H), 1.50 (m, 2H).

Example 16

Preparation of 2- (2- (2 - ((2- (2-pyridylamino) ethyl) amino) acetyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

Step A: Methyl 2- (2- (2-bromoacetyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate

To a stirred solution of methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate hydrochloride in THF (0.1 M) was added diisopropylethylamine (1.5 eq.). The reaction mixture was stirred for 15 minutes, followed by the addition of bromoacetyl bromide (1.1 eq.). To The reaction mixture was diluted with methylene chloride for 30 minutes and washed with 10% HCl, water and brine. The organic Layer was separated, over Dried sodium sulfate and concentrated by rotary evaporation. The residue was purified by flash chromatography (50% EtOAc / hexane).

Step B: Methyl 2- (2- (2- (2 - ((2- (2-Pyridylamino) ethyl) amino) acetyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate

To a stirred solution of methyl 2- (2- (2-bromoacetyl) -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate in THF (0.2M) was added diisopropylethylamine (1, 5 eq.) And 2- (2-pyridylamino) -1-aminoethane (1.2 eq.). The reaction mixture was stirred for 18 hours, followed by rotary evaporation, and the product was purified by flash chromatography (10% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 397 (MH) ⁺ .

Step C: 2- (2- (2- (2 - ((2- (2-Pyridylamino) ethyl) amino) acetyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

Methyl 2- (2- (2- (2 - ((2- (2-pyridylamino) ethyl) amino) acetyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate was prepared according to the method of Example 2 saponified. ¹ H-NMR (400 MHz, d4-CD ₃ OD): δ 7.90 (m, 2H), 7.43 to 7.11 (m, 5H), 6.97 (m, 1H), 4.69 (q, J = 18Hz, 2H), 4.19 (m, 1H), 3.83 (m, 2H), 3.65 (m, 1H), 3.55 (m, 1H), 3.38 (m, 2H); 3.34 (s, 2H), 2.83 (m, 2H), 2.04 (m, 1H), 1.69 (m, 1H).

Example 17

2- (2- (2 - ((3- (2-pyridylamino) prop-1-yl) amino) acetyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

2- (2- (2 - ((3- (2-pyridylamino) prop-1-yl) amino) acetyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid from 3- (2-pyridylamino) -1-aminopropane and methyl 2- (2- (2-bromoacetyl) -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate according to the method of Example 16 produced.
¹ H-NMR (400 MHz, d4-CD ₃ OD): δ 7.39 to 7.04 (m, 6H), 6.44 (m, 2H), 4.60 (m, 2H), 3.91 (m, 1H), 3.58 (m, 2H), 3.39 (m, 2H), 3.29 (s, 2H), 2.95 (m, 2H), 2.59 (m, 2H) , 1.95 (m, 1H), 1.85 (m, 2H), 1.60 (m, 2H).

Example 18

2- (2- (2 - ((4- (2-pyridylamino) but-1-yl) amino) acetyl-1H, 3H, 4H,5H-benzo [e] azapin-5-yl-acetic acid

2- (2- (2 - ((4- (2-pyridylamino) but-1-yl) amino) acetyl-1H, 3H, 4H, 5H-benzo [e] azapin-5-yl-acetic acid was prepared from (2-Pyridylamino) -1-aminobutane and methyl 2- (2- (2-bromoacetyl) -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate prepared according to the method of Example 16.
¹ H-NMR (400 MHz, d6-DMSO): δ 7.96 (m, 1H), 7.39-7.09 (m, 6H), 6.46 (m, 1H), 6.40 (m , 2H), 4.61 (m, 2H), 3.74 (s, 2H), 3.60 (m, 1H), 3.49 (m, 1H), 3.18 (m, 3H), 2 , 66 (m, 4H), 1.89 (m, 1H), 1.52 (m, 5H).

Example 19

2- (2 - ((N- (3- (2-pyridylamino) prop-1-yl) carbamoyl) methyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

2- (2 - ((N - (3- (2-Pyridylamino) propyl) carbamoyl) methyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate was prepared from 3- (2 Pyridylamino) -1- (2-bromoacetylamino) propane and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate hydrochloride in a similar manner to the procedure of Example 16 , Step B, prepared. 3- (2-Pyridylamino) -1- (2-bromoacetylamino) propane was prepared from 3- (2-pyridylamino) -1-aminopropane and bromoacetyl bromide in a similar manner to the procedure of Example 16, Step A. ¹ H-NMR (400 MHz, d6-DMSO): δ 7.90 (m, 1H), 7.82 (m, 1H), 7.30 (m, 1H), 7.16 (m, 1H), 7.08 (m, 3H), 6.44 (m, 1H), 6.39 (m, 2H), 3.86 (m, 2H), 3.43 (m, 1H), 3.24 (m , 2H), 3.18 (m, 2H), 3.02 (s, 2H), 2.86 (m, 2H), 2.70 (m, 2H), 1.65 (m, 1H), 1 , 60 (m, 3H).

Example 20

Preparation of 2- (2- (4- (2-pyridylamino) but-1-oxycarbonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

Step A: Methyl 2- (2- (4- (2-pyridylamino) but-1-oxycarbonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate

To a stirred solution of methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate hydrochloride in methylene chloride (0.2M) was added dimethylaminopyridine (2 eq.) And Add 4- (2-pyridylamino) butyl-4-nitrophenyl carbonate (1.1 eq.). The reaction mixture was stirred under nitrogen for 18 hours, diluted with methylene chloride, washed with sodium carbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (4% MeOH / CH ₂ Cl ₂ ) gave the product. EI-MS m / z 412 (M + H) ⁺ .

Step B: 2- (2- (4- (2-Pyridylamino) but-1-oxycarbonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

Methyl 2- (2- (4- (2-pyridylamino) but-1-oxycarbonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate was saponified according to the method of Example 2. EI-MS m / z 397 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.90 (m, 1H), 7.30 (m, 1H), 7.22-7.01 (m, 5H), 6.39 (m , 2H), 4.42 (q, J = 30Hz, 2H), 3.91 (m, 2H), 3.69 (m, 1H), 3.57 (m, 1H), 3.46 (m , 2H), 3.28 (m, 2H), 2.69 (m, 2H), 1.76 (m, 1H), 1.60 (m, 5H).

Example 21 (reference)

Preparation of methyl 2- (8-methoxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Step A: Methyl 2-bromo-5-methoxybenzoate

Sulfuric acid (2 eq.) Was added to a solution of 2-bromo-5-methoxybenzoic acid (1 eq.) In methanol (0.30 M) at 0 ° C under N ₂ . The solution was allowed to warm to RT and then refluxed for 5 hours. After cooling to rt, the solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and washed with 1N NaOH twice. The combined aqueous layers were extracted with ethyl acetate and the combined organics were dried over MgSO ₄ . Concentration under reduced pressure gave methyl 2-bromo-5-methoxybenzoate as a clear oil. EI-MS m / z 245, 247 (M + H) ⁺ .

Step B: 2-bromo-5-methoxybenzyl alcohol

Lithium aluminum hydride (1.3 eq.) Was added in portions to a solution of methyl 2-bromo-5-methoxybenzoate (1 eq.) In diethyl ether (0.35 M) at 0 ° C under N ₂ and the resulting mixture was allowed to warm to RT with stirring for 5 hours. The mixture was quenched with H ₂ O (1 x g LAH), followed by the sequential addition of 15% NaOH solution (3 x g LAH) and H ₂ O (3 x g LAH). The solution was filtered through a sintered glass funnel, which was rinsed with diethyl ether and concentrated under reduced pressure to give 2-bromo-5-methoxybenzyl alcohol as a clear oil. EI-MS m / z 239, 241 (M + Na) ⁺ .

Step C: 2-Bromo-5-methoxybenzaldehyde

Pyridinium chlorochromate (1.2 eq.) Was added to a solution of 2-bromo-5-methoxybenzyl alcohol (1 eq.) And celite (1.2 eq.) In methylene chloride (0.30 M) was added at RT and the resulting Mixture was stirred for 3 hours under nitrogen. The mixture was filtered through a silica plug, which was rinsed with methylene chloride, and concentrated under reduced pressure to give 2-bromo-5-methoxybenzaldehyde as a white solid. EI-MS m / z 232, 234 (M + NH ₄₎ ^+.

Step D: 3 - (((2-Bromo-5-methoxyphenyl) methyl) amino) propan-1-ol

To a stirred solution of 2-bromo-5-methoxybenzaldehyde (1 eq.) In dichloroethane was added 3-aminopropanol (1.5 eq.) Followed by NaBH (OAc) ₃ (2 eq.) And acetic acid (4 eq. ) and the resulting mixture was stirred under nitrogen for 8 hours at RT. The reaction mixture was quenched by careful addition of a 2M Na ₂ CO ₃ solution and stirred for 1 hour. The mixture was concentrated under reduced pressure and poured into diethyl ether. The phases were separated and the organic phase was washed with 1N HCl solution. The aqueous phase was then washed with diethyl ether and then basified with 1N NaOH solution. The aqueous phase was extracted with diethyl ether, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 3 - (((2-bromo-5-methoxyphenyl) methyl) amino) propan-1-ol as a clear oil.
EI-MS m / z 274, 276 (M + H) ⁺ .

Step E: N- (tert-butoxycarbonyl) -N - ((2-bromo-5-methoxyphenyl) methyl) -N- (3-hydroxypropyl) amine

Di-tert-butyl dicarbonate (1.1 eq.) Was added to a solution of 3 - (((2-bromo-5-methoxyphenyl) methyl) amino) propan-1-ol (1 eq.) In methylene chloride (0.30 M) at RT and the resulting mixture was stirred for 2 hours under nitrogen. Concentration under reduced pressure and purification by flash chromatography (20 to 30% ethyl acetate / hexane) gave N- (tert-butoxycarbonyl) -N - ((2-bromo-5-methoxyphenyl) methyl) -N- (3 hydroxypropyl) amine as a clear oil. EI-MS m / z 374, 376 (M + H) ⁺ .

Step F: Methyl (2E) -5 - ((tert -butoxy) -N - ((2-bromo-5-methoxyphenyl) methyl) carbonylamino) pent-2-enoate

Oxalyl chloride (1.8 eq.) Was added to a stirred solution of dimethylsulfoxide (3.8 eq.) In methylene chloride (0.25 M) at -78 ° C, maintaining the temperature at <-65 ° C. After 20 minutes, a solution of N- (tert-butoxycarbonyl) -N - ((2-bromo-5-methoxyphenyl) methyl) -N- (3-hydroxypropyl) amine (1 eq.) Was added and the resulting mixture became Stirred for 30 minutes. Hunig base (4 eq.) Was added and the reaction was allowed to warm to rt. The mixture was then cooled to 15 ° C and methyl (triphenylphosphoranylidene) acetate added. The resulting mixture was stirred for 12 hours and purified by flash chromatography on silica gel (10 to 20% ethyl acetate / hexane) to give methyl (2E) -5 - ((tert-butoxy) -N - ((2-bromo) 5-methoxyphenyl) methyl) carbonylamino) pent-2-enoate as a clear oil. EI-MS m / z 428, 430 (M + H) ⁺ .

Step G: Methyl 2- (2- (tert-butoxycarbonyl) -8-methoxy-1H, 3H, 4H-benzo [e] azaperhydroepin-5-ylidene) acetate

Triethylamine (1.5 eq.) Was added to a solution of methyl (2E) -5 - ((tert -butoxy) -N - ((2-bromo-5-methoxyphenyl) methyl) carbonylamino) pent-2-enoate ( 1 eq.), Palladium acetate (0.10 eq.) And tri-o-tolylphosphine (0.20 eq.) In acetonitrile (0.1 M), and the resulting mixture was refluxed under argon for 48 hours. Concentration under reduced pressure and purification by flash chromatography on silica gel (10 to 20% ethyl acetate / hexane) gave methyl 2- (2- (tert-butoxycarbonyl) -8-methoxy-1H, 3H, 4H-benzo [e ] azaperhydroepin-5-ylidene) acetate as a clear oil. EI-MS m / z 348 (M + H) ⁺ .

Step H: Methyl 2- (2- (tert-butoxycarbonyl) -8-methoxy-1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Magnesium turnings (10 eq.) Were added to a solution of methyl 2- (2- (tert-butoxycarbonyl) -8-methoxy-1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-ylidene) acetate (1 eq .) in methanol (0.1M) and the mixture was refluxed under nitrogen for 24 hours. After cooling to rt, the mixture was poured into 1N HCl and extracted with ethyl acetate. The organics were dried over magnesium sulfate and concentrated under reduced pressure to give methyl 2- (2 - ((tert-butyl) oxycarbonyl) -8-methoxy-1H, 3H, 4H, 5H-benzo [e] azaperhydroepine-5 -yl) acetate as a clear oil. EI-MS m / z 350 (M + H) ⁺ .

Step I: Methyl 2- (8-methoxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Methyl 2- (2- (tert-butoxycarbonyl) -8-methoxy-1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-ylacetate (1 eq.) And 4.0 M HCl / dioxane (12 eq The solvents were removed by rotary evaporation and the residue was dissolved in methylene chloride and washed with 1N NaOH The organics were dried over sodium sulfate and concentrated under reduced pressure to give methyl-2 - (8-methoxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate as a white solid, EI-MS m / z 250 (M + H) ⁺ .

Example 22

Preparation of 2- (8-Methoxy-2- (N- (4- (2-pyridylamino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetic acid

Step A: Methyl 2- (8-methoxy-2- (N- (4- (2-pyridylamino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5 yl) acetate

Methyl 2- (8-methoxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate (1 eq.) Was added under nitrogen with 20% phosgene (1.1 eq Toluene stirred for 10 minutes. The excess phosgene was removed by rotary evaporation and the crude product was dissolved in THF (0.10 M), followed by the addition of diisopropylethylamine (1.5 eq.) And 2- (4-aminobut-1-ylamino) pyridine (1 , 5 eq.). The reaction mixture was stirred under nitrogen for 12 h at RT, concentrated under reduced pressure, and the product was purified by flash chromatography (4 to 7% MeOH / CH ₂ Cl ₂ ) to give methyl 2- (8-methoxy-2 - (N- (4- (2-pyridylamino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate as a clear oil. EI-MS m / z 441 (M + H) ⁺ .

Step B: 2- (8-Methoxy-2- (N- (4- (2-pyridylamino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetic acid

1N NaOH solution (2 eq.) Was added to a solution of methyl 2- (8-methoxy-2- (N- (4- (2-pyridylamino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate (1 eq.) In methanol (0.05 M) was added and the resulting mixture was stirred for 12 h under nitrogen. The mixture was neutralized to pH = 7 with 1N HCl solution and concentrated under reduced pressure. Purification by flash chromatography on silica gel (20% MeOH / 80% CH ₃ Cl / 1% AcOH) gave 2- (8-methoxy-2- (N- (4- (2-pyridylamino) but-1-yl). carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetic acid as a white solid.
EI-MS m / z 427 (M + H) ⁺ ; ¹ H-NMR (400 MHz, D ₂ O): δ 7.76 (ddd, J = 8.8, 7.2, 1.4 Hz, 1H), 7.64 (d, J = 6.3 Hz , 1H), 6.98 (d, J = 8.5 Hz, 1H), 6.81 (m, 3H), 6.58 (dd, J = 8.4, 2.4 Hz, 1H), 4 , 38 (ABq, J = 16.0 Hz, 2H), 3.67 (s, 3H), 3.57 (m, 2H), 3.33 (m, 1H), 3.07 (m, 4H) , 2.63 (dd, J = 14.8, 8.2 Hz, 1H), 2.53 (dd, J = 14.8, 7.6 Hz, 1H), 1.81 (m, 1H), 1.55 (m, 1H), 1.40 (m, 2H), 1.27 (m, 2H).

Example 23 (reference)

Preparation of methyl 2- (8-fluoro-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Step A: 3 - (((2-Bromo-5-fluorophenyl) methyl) amino) propan-1-ol

Hunig base (1.3 eq.) And 3-aminopropan-1-ol (1.3 eq.) Were added to a solution of 2-bromo-5-fluorobenzylbromide (1 eq.) In acetonitrile (0.6 M) and the resulting mixture was stirred under nitrogen for 12 hours at RT. Concentration under reduced pressure gave 3 - (((2-bromo-5-fluorophenyl) methyl) amino) propan-1-ol as a clear oil.
EI-MS m / z 262, 264 (M + H) ⁺ .

Step B: N- (tert-butoxycarbonyl) -N - ((2-bromo-5-fluorophenyl) methyl) -N- (3-hydroxypropyl) amine

Di-tert-butyl dicarbonate (1.1 eq.) Was added to a solution of 3 - (((2-bromo-5-fluorophenyl) methyl) amino) propan-1-ol (1 eq.) In methylene chloride (0.50 M) at RT and the resulting mixture was stirred under nitrogen for 5 hours. Concentration under reduced pressure and purification by flash chromatography on silica gel (20 to 30% ethyl acetate / hexane) gave N- (tert-butoxycarbonyl) -N - ((2-bromo-5-fluorophenyl) methyl) -N- ( 3-hydroxypropyl) amine as a clear oil. EI-MS m / z 362, 364 (M + H) ⁺ .

Step C: Methyl (2E) -5- (N- (tert-butoxycarbonyl) -N - ((2-bromo-5-fluorophenyl) methyl) amino) pent-2-enoate

Oxalyl chloride (1.8 eq.) Was added to a stirred solution of dimethylsulfoxide (3.8 eq.) In methylene chloride (0.25 M) at -78 ° C, maintaining the temperature at <-65 ° C. After 20 minutes, a solution of N- (tert-butoxycarbonyl) -N - ((2-bromo-5-fluorophenyl) methyl) -N- (3-hydroxypropyl) amine (1 eq.) Was added and the resulting mixture became Stirred for 30 minutes. Hunig base (4 eq.) Was added and the reaction was allowed to warm to rt. The mixture was then cooled to 15 ° C and methyl (triphenylphosphoranylidene) acetate added. The resulting mixture was stirred for 12 hours and purified by flash chromatography on silica gel (10 to 20% ethyl acetate / hexane) to give methyl (2E) -5- (N- (tert-butoxycarbonyl) -N - (2- bromo-5-fluorophenyl) methyl) amino) pent-2-enoate as a clear oil. EI-MS m / z 474, 476 (M-H + HOAc) ^- .

Step D: Methyl 2- (2- (tert-butoxycarbonyl) -8-fluoro-1H, 3H, 4H-benzo [e] azaperhydroepin-5-ylidene) acetate

Triethylamine (1.5 eq.) Was added to a solution of methyl (2E) -5- (N- (tert-butoxycarbonyl) -N - ((2-bromo-5-fluorophenyl) methyl) amino) pent-2-one. enoate (1 eq.), palladium acetate (0.10 eq.) and tri-o-tolylphosphine (0.20 eq.) in acetonitrile (0.1 M), and the resulting mixture was refluxed under argon for 48 hours , Concentration under reduced pressure and purification by flash chromatography on silica gel (5 to 10% ethyl acetate / hexane) gave methyl 2- (2- (tert-butoxycarbonyl) -8-fluoro-1H, 3H, 4H-benzo [e ] azaperhydroepin-5-ylidene) acetate as a clear oil. EI-MS m / z (M + H) ⁺ .

Step E: Methyl 2- (2- (tert-butoxycarbonyl) -8-fluoro-1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Magnesium turnings (10 eq.) Were added to a solution of methyl 2- (2- (tert-butoxycarbonyl) -8-fluoro-1H, 3H, 4H-benzo [e] azaperhydroepin-5-ylidene) acetate (1 eq.). in methanol (0.1M) and the mixture was refluxed under nitrogen for 24 hours. After cooling to rt, the mixture was poured into 1N HCl and extracted with ethyl acetate. The organics were dried over magnesium sulfate and concentrated under reduced pressure to give methyl 2- (2- (tert-butoxycarbonyl) -8-fluoro-1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl). acetate as a clear oil. EI-MS m / z 338 (M + H) ⁺ .

Step F: Methyl 2- (8-fluoro-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Methyl 2- (2- (tert-butoxycarbonyl) -8-fluoro-1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate (1 eq.) And 4.0 M HCl / dioxane ( 12 eq.) Were stirred under nitrogen for 3 hours at RT. The solvents were removed by rotary evaporation and the residue was dissolved in methylene chloride and washed with 1N NaOH. The organics were dried over sodium sulfate and concentrated under reduced pressure to give methyl 2- (8-fluoro-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate as a clear oil. EI-MS m / z 238 (M + H) ⁺ .

Example 24

Preparation of 2- (8-Fluoro-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H , 5H-benzo [e] azaperhydroepin-5-yl) acetic acid

Step A: Methyl 2- (8-fluoro-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Methyl 2- (8-fluoro-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate (1 eq.) Was added under nitrogen with 20% phosgene (1.1 eq.) In Toluene stirred for 10 minutes. The excess phosgene was removed by rotary evaporation and the crude product was dissolved in 1: 1 THF / DMF (0.25 M) followed by the addition of diisopropylethylamine (1.1 eq.) And 3- (1,2,3, 4-Tetrahydropyridino [2,3, b] pyridin-7-yl) propylamine (1.1 eq.). The reaction mixture was stirred under nitrogen for 12 h at rt, concentrated under reduced pressure, and the product was purified by flash chromatography (2 to 5% MeOH / CH ₃ Cl) to give methyl 2- (8-fluoro-2-). (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5 yl) acetate as a clear oil.
EI-MS m / z 455 (M + H) ⁺ .

Step B: 2- (8-Fluoro-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepim-5-yl) acetic acid

1 N NaOH solution (3 eq.) Was added to a solution of methyl 2- (8-fluoro-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridine -7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepim-5-yl) acetate (1 eq.) In methanol (0.10M) and the resulting mixture became 12 Stirred under nitrogen for hours. The mixture was neutralized to pH = 7 with 1N HCl solution and concentrated under reduced pressure. Purification by flash chromatography on silica gel (4 to 6% MeOH / CH ₂ Cl ₂ ) gave 2- (8-fluoro-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3 , b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetic acid as a white solid. EI-MS m / z 441 (M + H) ⁺ ; ¹ H-NMR (400 MHz, CDCl _3): δ 10.56 (br s, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.12 (dd, J = 8.4 , 5.8 Hz, 1H), 6.93 (dd, J = 9.2, 2.2 Hz, 1H), 6.86 (t, J = 8.4 Hz, 1H), 6.27 (i.e. , J = 7.3Hz, 1H), 5.55 (brs, 1H), 4.90 (brs, 1H), 4.35 (d, J = 15.2Hz, 2H), 3.50 (m, 4H), 3.27 (m, 1H), 3.11 (m, 1H), 2.67 (m, 6H), 2.35 (m, 1H), 1.90 (m, 4H) , 1.74 (m, 1H), 1.42 (m, 1H).

Example 25 (reference)

Preparation of 2- (2 - ({N - (4- (2-pyridylamino) -prop-1-yl) -carbamyl} -methyl) -3-oxo-1H, 4H, 5H-benzo (e) azepin-5-yl) acetic acid

Step A: trans-glutaconic acid methyl ester

To a stirred solution of glutaconic acid in DMF (0.1 M) at 0 ° C was added NaH (1 eq.). After 15 minutes, iodomethane (1.2 eq.) Was added and the mixture was allowed to warm to room temperature overnight. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed (silica, 10% MeOH / CHCl ₃ ) to give a colorless viscous oil. EI-MS m / z 143 (MH) ^- .

Step B: Benzene-2- (N- (2-bromophenylmethyl) amino) acetate

To a stirred solution of 2-bromobenzaldehyde in dichloromethane (0.2 M) was added glycine benzyl ester (1.2 eq.), Sodium triacetoxyborohydride (2 eq.) And acetic acid (4 eq.). After stirring overnight, the solution was washed with 10% sodium carbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed (silica, 30-40% EtOAc / hexanes) to give a pale yellow oil. EI-MS m / z 334, 336 (M + H) ⁺ .

Step C: Benzene-2- (N - ((3- (methoxycarbonyl) propene-1-yl) carbonyl) -N- (2-bromophenylmethyl) amino) acetate

Benzyl 2- (N- (2-bromophenylmethyl) amino) acetate was dissolved in dichloromethane (0.2 M) followed by the addition of trans -gluconic acid methyl ester (1.2 eq.), Triethylamine (2 eq.), EDAC (1.2 eq.) And HORT (0.1 eq.). After stirring for 2 hours, the solution was washed with 10% HCl, 10% sodium carbonate, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (50% EtOAc / Hex) gave a viscous oil. EI-MS m / z 460, 462 (M + H) ⁺ .

Step D: Methyl 2- (2 - ((phenylmethoxycarbonyl) methyl) -3-oxo-1H, 4H-benzo [e] azaperhydroepin-5-ylidene) acetate

Benzyl 2- (N - ((3- (methoxycarbonyl) propene-1-yl) carbonyl) -N- (2-bromophenylmethyl) amino) acetate was dissolved in toluene (0.1 M) followed by the addition of triethylamine (1.2 eq.) And tetrakis (triphenylphosphine) palladium (0.05 eq.), And the solution was stirred at reflux overnight. The reaction mixture was washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography (silica, 50% EtOAc / Hex) gave a viscous oil.
EI-MS m / z 380 (M + H) ⁺ .

Step E: Methyl 2- (2- (carboxymethyl) -3-oxo-1H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

The olefin was dissolved in methanol followed by the addition of 10% palladium on carbon (10% by weight) and hydrogenation on a Parr shaker at 50 psi. After 8 hours, the mixture was filtered through celite and concentrated under reduced pressure to give a viscous oil. EI-MS m / z 292 (M + H) ⁺ .

Step F: Methyl 2- (2 - ({N- (4- (2-pyridylamino) -prop-1-yl) carbamoyl} methyl-3-oxo-1H, 4H, 5H-benzo (e) azepine-5 yl) acetate

Methyl 2- (2- (carboxymethyl) -3-oxo-1H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate was dissolved in dichloromethane (0.2 M) followed by the addition of 2- (3-aminoprop-1-ylamino) pyridine (1.2 eq.), Hunig's base (1.5 eq.) And EDAC (1.2 eq.). After stirring for 2 hours, the reaction mixture was washed with 10% sodium carbonate, water and brine, dried over magnesium sulfate, filtered and concentrated. Flash chromatography (silica: 10% MeOH / CHCl ₃ ) gave a colorless solid. EI-MS m / z 425 (M + H) ⁺ .

Step G: 2- (2 - ({N - (4- (2-Pyridylamino) -prop-1-yl) carbamoyl} methyl) -3-oxo-1H, 4H, 5H-benzo (e) azepin-5-yl )acetic acid

Methyl-2- (2 - ({N- (4- (2-pyridylamino) prop-1-yl) carbamoyl} methyl) -3-oxo-1H, 4H, 5H-benzo (e) azepin-5-yl) acetate was dissolved in MeOH, followed by the addition of 1N NaOH (5 eq.), and the solution became stirred overnight. 1N HCl (5 eq.) Was added and the reaction mixture was concentrated under reduced pressure. Flash chromatography (silica, 10% MeOH / CHCl ₃ ) gave the title compound as a colorless solid. EI-MS m / z 411 (M + H); ¹ H-NMR (400 MHz, D ₂ O): 7.62 (1H, t, J = 8.1 Hz), 7.53 (1H, d, J = 6.0 Hz), 7.10 (4H , m), 6.74 (1H, d, J = 9.1 Hz), 6.62 (1H, t, J = 6.8 Hz), 4.67 (1H, d, J = 16 Hz), 4.22 (1H, d, J = 16 Hz), 3.95 (2H, m), 3.42 (1H, t, J = 6.9 Hz), 3.12 (4H, m), 2, 0-1.8 (4H, m), 1.65 (2H, m).

Example 26 (reference)

Preparation of methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [d] azepin-1-yl) acetate

Step A: 2- (2-Bromophenol) -N- (phenylmethyl) acetamide

To a stirred solution of 2-bromophenylacetic acid in dichloromethane (0.2 M) was added benzylamine (1.2 eq.), Triethylamine (1.5 eq.) And EDAC (1.5 eq.). After 2 hours, the solution was washed with water, 10% HCl, 10% sodium carbonate and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a colorless solid. EI-MS m / z 304/306 (M + H) ⁺ .

Step B: N- (2- (2-Bromophenol) ethyl) -N- (phenylmethyl) amine

2- (2-bromophenyl) -N- (phenylmethyl) acetamide was dissolved in THF (0.2 M), followed by the addition of BH ₃ · DMS (3 eq.) And the reaction mixture was heated with stirring to reflux. After 2 hours, the mixture was cooled to room temperature and quenched with an excess of 10% HCl. The mixture was heated at reflux for 1 hour and then cooled to room temperature. After washing with EtOAc, the aqueous phase was basified with 10% sodium carbonate and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with EtOAc to give a colorless solid. EI-MS m / z 290/292 (M + H) ⁺ .

Step C: Methyl 4- (N- (phenylmethyl) -N - ((2-bromophenyl) methyl) amino) but-2-enoate

N- (2- (2-Bromophenyl) ethyl) -N- (phenylmethyl) amine was dissolved in acetonitrile (0.2 M) followed by the addition of methyl 4-bromocrotonate (1.2 eq) and triethylamine ( 1.5 eq.), And the reaction mixture was heated at reflux overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with 10% sodium carbonate, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (silica, 50% EtOAc / Hex) gave a colorless oil. EI-MS m / z 388/390 (M + H) ⁺ .

Step D: Methyl 2- (3- (phenylmethyl) -2H, 4H, 5H-benzo [d] azaperhydroepin-1-ylidene) acetate

Methyl 4- (N- (phenylmethyl) -N - ((2-bromophenyl) methyl) amino) but-2-enoate was dissolved in toluene (0.1 M) followed by the addition of triethylamine (1 eq.). , Tetrakis (triphenylphosphine) palladium (0.05 eq.) And 2 M sodium carbonate (15% by volume). The mixture was heated to reflux with vigorous stirring overnight. After cooling to room temperature the phases were separated and the organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in EtOAc and extracted five times with 6N HCl. The combined extracts were neutralized with 10% sodium carbonate and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a yellow oil. EI-MS m / z 208 (M + H) ⁺ .

Step E: Methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [d] azepin-1-yl) acetate

Methyl 2- (3- (phenylmethyl) -2H, 4H, 5H-benzo [d] azaperhydroepin-1-ylidene) acetate was dissolved in MeOH (0.1 M), followed by the addition of p-toluenesulfonic acid (1 eq ) and 10% palladium on carbon (50%, by weight), and the mixture was subjected to hydrogenation overnight on a Parr shaker at 50 psi. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with 10% sodium carbonate and brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a colorless oil. EI-MS m / z 220 (M + H) ⁺ .

Example 27

Preparation of 2- (3 - ({N- (4- (2-pyridylamino) but-1-yl) carbamoyl} methyl) -1H, 2H, 4H, 5H-benzo [d] azepin-1-yl) acetic acid

Step A: Methyl 2- (3 - ({N- (4- (2-pyridylamino) but-1-yl) carbamoyl} methyl) -1H, 2H, 4H, 5H-benzo [d] azepin-1-yl )acetate

To a stirred solution of methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [d] azepin-1-yl) acetate in acetonitrile (0.2M) was added Hunig's base (1.5 eq.), followed by bromoacetic acid. After stirring for 2 h, 2 - ((4-aminobut-1-yl) amino) pyridine (1.2 eq.) Was added followed by Hunigscher base (1.5 eq.) And EDAC (1.5 eq.). and stirring was continued for a further 2 hours. The reaction mixture was diluted with EtOAc and washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (silica, 10% MeOH / EtOAc) gave a colorless solid. EI-MS m / z 425 (M + H) ⁺ .

Step B: 2- (3 - ((N- (4- (2-pyridylamino) but-1-yl) carbamoyl) methyl) -1H, 2H, 4H, 5H-benzo [d] azepin-1-yl) acetic acid

Methyl 2- (3 - ({N- (4- (2-pyridylamino) but-1-yl) carbamoyl} methyl) -1H, 2H, 4H, 5H-benzo [d] azepin-1-yl) acetate in MeOH (0.1 M), followed by the addition of 1 N NaOH (5 eq.). After stirring overnight, 1N HCl (5 eq.) Was added and the solution was concentrated under reduced pressure. Flash chromatography (10% MeOH / CHCl ₃ ) gave a colorless solid. EI-MS m / z 411 (M + H) ⁺ ; ¹ H-NMR (400 MHz, D ₂ O): 7.50 (2H, m), 6.93 (4H, m), 6.62 (1H, d, J = 8.9 Hz), 6.51 (1H, t, J = 6.7 Hz), 3.23 (1H, m), 3.01 (6H, m), 2.75 (2H, br), 2.57 (4H, m), 2 , 38 (2H, m), 1.36 (4H, br).

Example 28

2- (3 - {[N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] methyl} -1H, 2H, 4H, 5H- benzo [d] azepinyl) acetic acid

2- (3 - {[N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] methyl} -1H, 2H, 4H, 5H- benzo [d] azepinyl) acetic acid was prepared from bromoacetic acid, 3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propylamine and methyl 2- (1H, 2H, 3H, 4H , 5H-benzo [d] azepin-1-yl) acetate prepared according to the method of Example 27. EI-MS m / z 437 (M + H) ⁺ ; ¹ H-NMR (400 MHz; CDCl _3): 9.61 (1H, br), 8.39 (1H, br), 7.15 (5H, m), 6.31 (1H, d, J = 7 , 25 Hz), 3.64 (2H, m), 3.34 (6H, m), 2.99 (4H, m), 2.71 (4H, m), 1.93 (5H, m), 0.86 (2H, m).

Example 29

2- (3- {N- (5- (2-pyridylamino) pent-1-yl) carbamoyl} -1H, 2H, 4H, 5H-benzo [d] azepinyl) acetic acid

2- (3- {N- (5- (2-Pyridylamino) pent-1-yl) carbamoyl} -1H, 2H, 4H, 5H-benzo [d] azepinyl) acetic acid was prepared from methyl 2- (1H, 2H , 3H, 4H, 5H-benzo [d] azepin-1-yl) acetate and 2 - ((5-aminopent-1-yl) amino) pyridine according to the method of Example 2. EI-MS m / z 411 (M + H) ⁺ ; ¹ H-NMR (400 MHz, D ₂ O): 7.42 (1H, d, J = 6.02 Hz), 7.33 (1H, t, J = 8.01 Hz), 6.82 (4H , m), 6.46 (1H, d, J = 8.90 Hz), 6.40 (1H, t, J = 6.9 Hz), 3.18 (5H, m), 2.90 (2H , t, J = 6.80 Hz), 2.72 (3H, m), 2.51 (1H, dt, J = 15.11 Hz, 4.42 Hz), 2.18 (2H, m), 1.23 (2H, m), 1.06 (2H, m), 0.94 (2H, m).

Example 30

2- {3- (N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl) -1H, 2H, 4H, 5H-benzo [d ] azepin-1-yl} acetic acid

2- {3- (N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl) -1H, 2H, 4H, 5H-benzo [d ] azepin-1-yl} acetic acid was prepared from methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [d] azepin-1-yl) acetate and 3- (1,2,3,4-tetrahydropyridino [ 2,3-b] pyridin-7-yl) propylamine according to the method of Example 2. EI-MS m / z 423 (M + H) ⁺ ; ¹ H-NMR (400 MHz, CDCl _3): 11.10 (1H, br), 7.86 (1H, br), 7.28-7.14 (5H, m), 6.32 (1H, d , J = 7.18 Hz), 4.79 (1H, br), 4.10 (1H, br), 3.48 (5H, m), 3.2-2.6 (10H, m), 2.08 (1H, m), 1.90 (4H, m).

Example 31 (reference)

7- (2-pyridylamino) heptanoic acid

To a stirred solution of 7-aminoheptanoic acid in pyridine (0.5 M) was added 2-fluoropyridine (2 eq.) And 2N NaOH (1 eq.), And the reaction was heated to reflux overnight. The mixture was adjusted to neutral pH with 6N HCl and concentrated under reduced pressure. The residue was suspended in 10: 1: 1 EtOH / NH ₄ OH / H ₂ O, filtered through a pad of silica and concentrated under reduced pressure to give a colorless solid.

Example 32

Preparation of 2- {3- (7- (2-pyridylamino) -heptanoyl) 1H, 2H, 4H, 5H-benzo [d] azepin-1-yl} acetic acid

Step A: Methyl 2- {3- (7- (2-Pyridylamino) -heptanoyl) -1H, 2H, 4H, 5H-benzo [d] azepin-1-yl} acetate

To a stirred solution of methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [d] azepin-1-yl) acetate in dichloromethane (0.2M) were added 7- (2-pyridylamino) heptanoic acid (1.2 eq.), Triethylamine (1.5 eq.) And EDAC (2 eq.) added. After 4 hours, the reaction mixture was water and 10% sodium carbonate, over anhydrous magnesium sulfate dried, filtered and concentrated under reduced pressure. Flash chromatography (silica, EtOAc) gave a colorless oil.

Step B: 2- {3- (7- (2-Pyridylamino) -heptanoyl) -1H, 2H, 4H, 5H-benzo [d] azepin-1-yl} acetic acid

Methyl 2- {3- (7- (2-pyridylamino) -heptanoyl) -1H, 2H, 4H, 5H-benzo [d] azepin-1-yl} acetate was dissolved in MeOH and 1N NaOH (5 eq. ) was added. After stirring overnight, 1N HCl (5 eq.) Was added and the reaction mixture was concentrated under reduced pressure. Flash chromatography (silica, 10% MeOH / CHCl ₃ ) gave a colorless solid. The sodium salt was prepared by dissolving the compound in MeOH (0.1 M), adding NaOMe (1.0 eq, 0.5 M in ME) and concentrating under reduced pressure to give a colorless solid. ESI MS m / z 432 (M + H) ⁺ ; ¹ H-NMR (400 MHz, DMSO-d ₆ ): 7.98 (1H, m), 7.33 (1H, m), 7.2-7.10 (4H, m), 6.60 (1H , d, J = 8.4 Hz), 6.43 (1H, m), 3.71 (2H, m), 3.49 (2H, m), 3.24 (2H, m), 2.90 (3H, m), 2.40 (2H, m), 2.24 (2H, m), 2.07 (1H, m), 1.53 (4H, m), 1.20 (4H, m) ,

Example 33

Preparation of 2- {6- (N- (3- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-yl) -propyl) -carbamoyl) -5H, 7H, 8H, 9H-pyridino [2,3-e] azaperhydroepin-9-yl} acetic acid

Step A: N - ((2-Bromo (3-pyridyl)) methyl) -2- (1,3-dioxolan-2-yl) ethylamine

To a solution of 2-bromopyridine-3-carbaldehyde (3.53 g, 19.0 mmol, 1.0 eq.) (Melnyk et al., Synthetic Commun. 23 (19): 2727-2730, 1993) in FIG , 2-dichloroethane (50 ml) were added 2- (1,3-dioxolan-2-yl) ethylamine (TCI-GR, 2.67 g, 22.8 mmol, 1.2 eq.), Sodium triacetoxyborohydride (Aldrich, 1 , 61 g, 76 mmol, 4.0 eq.) And glacial acetic acid (1.14 g, 19 mmol, 1.0 eq.). The reaction mixture was stirred under nitrogen for 2 hours at room temperature. The reaction was quenched with 1.0 N aqueous NaOH to about pH 8 and the solution was extracted with EtOAc (200 mL x 3). The organic extracts were washed with saturated NaCl, dried over MgSO ₄ , filtered and concentrated. Flash column chromatography (silica gel, 0-10% EtOAc-hexane) gave the title compound as a colorless oil. MS m / z 377 (Br = 79, M + H), 379 (Br = 81, M + H).

Step B: N - ((2-Bromo (3-pyridyl) methyl) - N - (2- (1,3-dioxolan-2-yl) ethyl) (phenylmethoxy) carboxamide

A biphasic mixture of N - ((2-bromo (3-pyridyl)) methyl) -2- (1,3-dioxolan-2-yl) ethylamine (4.15 g, 14.4 mmol, 1.0 eq. ), Benzyl chloroformate (Aldrich, 3.70 g, 21.7 mmol, 1.5 eq.) And Na ₂ CO ₃ (3.05 g, 28.8 mmol, 2.0 eq.), CH ₂ Cl ₂ ( 20 ml) and H ₂ O (20 ml) was stirred at room temperature overnight. The reaction mixture was diluted with H ₂ O (50 mL) and extracted with CH ₂ Cl ₂ (60 mL x 3). The organic extracts were washed with brine, dried with Na ₂ SO ₄ , filtered and concentrated. Flash column chromatography (silica gel, 0 to 50% EtOAc-hexane) gave the title compound as a colorless oil. MS m / z 421 (Br = 79, M + H), 423 (Br = 81, M + H).

Step C: N - ((2-Bromo (3-pyridyl) methyl) -N- (3-oxobutyl) (phenylmethoxy) carboxamide

A solution of N - ((2-bromo (3-pyridyl) methyl) -N- (2- (1,3-dioxolan-2-yl) ethyl) (phenylmethoxy) carboxamide in a mixture of 5% aqueous HCl (50 The acetone was removed under reduced pressure and the aqueous reaction mixture was extracted with EtOAc (70 mL x 3) The organic extracts were washed with brine, Na ₂ SO ₄ Flash column chromatography (silica gel (0 to 50% EtOAc-hexane) gave the title compound as a colorless Cl. MS m / z 376 (Br = 79, M + H), 378 (Br = 81, M + H).

Step D: Methyl (2E) -5- {N - ((2-bromo (3-pyridyl) methyl) -N- (phenylmethoxycarbonyl) amino} pent-2-enoate

To a solution of N - ((2-bromo (3-pyridyl) methyl) - N - (3-oxobutyl) (phenylmethoxy) carboxamide (4.83 g, 12.8 mmol, 1.0 eq.) In CH ₂ Cl ₂ ) (20 mL) at room temperature was added a solution of carbomethoxymethylenetriphenylphosphorane (avocado, 4.92 g, 14.7 mmol, 1.15 eq.) In CH ₂ Cl ₂ (50 mL) via cannula. The reaction mixture was stirred under nitrogen for 6 hours at room temperature. The solvent was removed under reduced pressure. Flash column chromatography (silica gel, 0 to 50% EtOAc-hexane) gave the title compound as a colorless oil. MS m / z 433 (Br = 79, M + H), 435 (Br = 81, M + H).

Step E: Methyl 2- {6- (benzyloxycarbonyl) -5H, 7H, 8H-pyrido [2,3-e] azaperhydroepin-9-ylidene acetate

A mixture of methyl (2E) -5- {N - ((2-bromo (3-pyridyl) methyl) -N- (phenylmethoxycarbonyl) amino} pent-2-enoate (650 mg, 1.50 mmol, 1, 0 eq.), Tetrakis (triphenylphosphine) palladium (0) (Aldrich, 581 mg, 0.50 mmol, 0.33 eq.), Triethylamine (540 mg, 4.5 mmol, 3.0 eq.), Aqueous sodium carbonate (8 mL, 2.0 M) in toluene (23.0 mL) in a sealed vessel was stirred for 48 hours at 120 ° C. The reaction mixture was diluted with CH ₂ Cl ₂ (40 mL) and passed through a celite pad The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (40 mL × 2) The combined organic layer was dried with Na ₂ SO ₄ , filtered and dried under reduced pressure. 0.1% TFA-H ₂ O / CH ₃ CN) gave the title compound as a colorless semi-solid MS MS / z 353 (M + H).

Step F: Methyl 2- (5H, 6H, 7H, 8H-pyridino [2,3-e] azaperhydroepin-9-ylidene) acetate

A mixture of methyl 2- {6- (benzyloxycarbonyl) -5H, 7H, 8H-pyrido [2,3-e] azaperhydroepin-9-ylidene} acetate (127 mg, 0.36 mmol, 1.0 eq.). Ammonium formate (Sigma, 192 mg, 2.72 mmol, 8.0 eq.) And 10% Pd / C (24 mg) in a mixture of solvents (10 mL methanol and 5 mL H ₂ O) was stirred at room temperature for 3 hours touched. Methanol was removed under reduced pressure. The residual aqueous layer was diluted with aqueous sodium carbonate (2.0 M, 20 mL) and extracted with CH ₂ Cl ₂ (30 mL x 3). The organic extracts were dried with Na ₂ SO ₄ , filtered and concentrated. Preparative thin layer chromatography (5% methanol + 0.5% ammonium hydroxide-CH ₂ Cl ₂ ) gave the title compound as a colorless semi-solid. MS m / z 219 (M + H).

Step G: Methyl 2- (5H, 6H, 7H, 8H, 9H-pyridino [2,3-e] azaperhydroepin-9-yl) acetate

A mixture of methyl 2- (5H, 6H, 7H, 8H-pyridino [2,3-e] azaperhydroepin-9-ylidene) acetate (35 mg, 0.16 mmol, 1.0 eq.) And magnesium (Aldrich , Powder, 42 mg, 1.73 mmol, 11 eq.) In methanol (1.65 ml) was stirred for 20 hours. After dilution of the reaction mixture with methanol, it was passed through a celite pad and concentrated under reduced pressure. Preparative thin layer chromatography (5% methanol + 0.5% ammonium hydroxide-CH ₂ Cl ₂ ) gave the title compound as a colorless sticky solid. MS m / z 221 (M + H).

Step H: Methyl 2- {6- (N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl) -5H, 7H, 8H, 9H-pyridino [2,3-e] azaperhydroepin-9-yl} acetate

To a mixture of methyl 2- (5H, 6H, 7H, 8H, 9H-pyridino [2,3-e] azaperhydroepin-9-yl) acetate (16 mg, 0.073 mmol, 1.0 eq.) In THF ( 0.5 ml) was added a solution of phosgene (Fluka, 1.0 ml, 20% in toluene) and diisopropylethylamine (38 mg, 0.29 mmol, 4.0 eq.). The reaction mixture was stirred for 10 minutes at room temperature. The solvents were removed under reduced pressure. The newly formed intermediate was dissolved in THF (1 ml), followed by the addition of a solution of 3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propylamine (0.212 ml, 1.1 M in THF / DMF, 0.23 mmol, 3.2 eq.) And diisopropylethylamine (38 mg, 0.29 mmol, 4.0 eq.). The reaction mixture was stirred at room temperature overnight. Preparative thin layer chromatography (5% MeOH + 0.25% triethylamine-CH ₂ Cl ₂ ) gave the title compound as a colorless semi-solid. MS m / z 438 (M + H).

Step I: 2- {6- (N- (3- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl) -5H, 7H, 8H, 9H- pyridino [2,3-e] azaperhydroepin-9-yl} acetic acid

To a solution of methyl 2- {6- (N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) -propyl) carbamoyl) -5H, 7H, 8H , 9H-Pyridino [2,3-e] azaperhydroepin-9-yl} acetate (11.1 mg, 0.254 mmol, 1.0 eq.) In ethanol (0.30 mL) was added a NaOH solution (0.028 mL, 2.0 M, 0.055 mmol, 2.2 eq.) And stirred at 55 ° C for 24 hours. After neutralization of the reaction mixture with a solution of HCl (0.028 mL, 2.0 N), all solvents were removed under reduced pressure. The crude product was triturated with 10% MeOH-CH ₂ Cl ₂ , filtered and concentrated under reduced pressure to give the title compound as a colorless sticky solid. ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.32 (m, 1), 7.67 (d, 1, J = 7.5 Hz), 7.44 (d, 1, J = 7 , 3), 7.18 (m, 1), 6.49 (d, 1, J = 7.3), 4.78 (d, 1, J = 15.6), 4.53 (d, 1 , J = 15.6), 3.68 (m, 1), 3.55 (m, 2), 3.45 (t, 2, J = 5.7), 3.34 (s, 1), 3.17 (m, 1), 2.97 (dd, 1, J = 5.2, 15.6), 2.77 (t, 2, J = 6.1), 2.61 (m, 3 ), 2.28 (m, 1), 1.80 (m, 2), 1.58 (m, 1), 1.31 (m, 1), 1.13 (m, 1). MS m / z 424 (M + H). HRMS m / z 424.2343 (M + H, C ₂₃ H ₂₉ N ₅ O ₃ , calc. 424.2349).

Example 34

Preparation of 2- (2- (N- (4- (2-pyridylamino-3-nitro-4-methyl) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapine-5 yl) acetic acid

Step A: 2- (N- (4-Aminoprop-1-yl) amino-3-nitro-4-methyl) pyridine

To a stirred solution of 2-chloro-3-nitro-4-methylpyridine in pyridine (0.5 M) was added 1,4-butanediamine (5 eq.) And the solution was refluxed for 18 hours. The solution was then concentrated under reduced pressure and the residue was partitioned between ethyl acetate and 10% sodium carbonate. The phases were separated and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed (silica, 10: 1: 1 ETOH / NH ₄ OH / H ₂ O) to give a viscous pale yellow oil. EI-MS m / z 152 (M + H) ⁺ .

Step B: Methyl 2- (2- (N- (4- (2-pyridylamino-3-nitro-4-methyl) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate

Methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate hydrochloride was dissolved in methylene chloride and washed with 1N NaOH. The organic layer was separated, dried over sodium sulfate and concentrated by rotary evaporation. The residue was stirred under nitrogen with 20% phosgene in toluene (0.1 M) for 10 minutes. After stirring, the reaction mixture was replaced by Rotati concentrated on evaporation, the residue was dissolved in THF (0.1 M), followed by the addition of diisopropylethylamine (1.5 eq.) and 2- (N- (4-aminoprop-1-yl) amino-3-nitro- 4-methyl) pyridine (1.2 eq.). The reaction mixture was stirred under nitrogen for 18 hours, followed by rotary evaporation, and the product was purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 397 (M + H).

Step C: 2- (2- (N- (4- (2-Pyridylamino-3-nitro-4-methyl) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapine 5-yl) acetic acid

To a stirred solution of methyl 2- (2- (N- (4- (2-pyridylamino-3-nitro-4-methyl) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e ] azapin-5-yl) acetate in methanol (0.1 M) was added 1 N NaOH (3 eq.). After 18 hours, the reaction mixture was neutralized with 10% HCl, concentrated by rotary evaporation, and purified by recrystallization from 2% MeOH / CH ₂ Cl ₂ . EI-MS m / z 456 (M + H) ⁺ ; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 11.0 (br s, 1H), 8.12 (d, J = 4.9 Hz, 1H), 7.52 (t, J = 4.6 Hz, 1H), 7.19 (m, 4H), 6.46 (d, J = 4.9 Hz, 1H), 4.77 (m, 1H), 4.48 (q, J = 15.2 Hz, 2H), 3.65 (m, 1H), 3.49 (m, 4H), 3.23 (m, 2H), 2.76 (m, 2H), 2.52 (s, 3H), 2.03 (m, 1H), 1.58 (m, 5H).

Example 35

Preparation of ethyl 2- (2- (N- (3- (2-pyridylamino) butyl-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate

Ethyl 2- (2- (N- (4- (2-pyridylamino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate was obtained from 2- (N- (4-Aminobut-1-yl) amino) pyridine and ethyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate were prepared according to the method of Example 34. Ethyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate was prepared by transesterification of methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin -5-yl) acetate with HCl and ethanol. EI-MS m / z 425 (M + H) ⁺ ; ¹ H-NMR (400 MHz, CDCl _3): δ 8.08 (d, J = 4.7 Hz, 1H), 7.40 (t, J = 12.1 Hz, 1H), 7.33 to 7 , 12 (m, 4H), 6.53 (t, J = 6.1 Hz, 1H), 6.33 (d, J = 8.3 Hz, 1H), 4.52 (d, J = 15, 3 Hz, 2H), 4.41 (s, 2H), 4.13 (q, J = 21.4 Hz, 2H), 3.70 (s, 1H), 3.60 (m, 2H), 3 , 28 (m, 4H), 2.81 (m, 1H), 2.70 (m, 1H), 2.05 (m, 1H), 1.64 (m, 1H), 1.25 (t, J = 7.10 Hz, 3H).

Example 36

Preparation of methyl 2- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H -benzo [e] azapin-5-yl) propanoate

Step A: Methyl 2- (2- (tert-butoxycarbonyl) -1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) propanoate

Methyl 2- (2- (tert-butoxycarbonyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate was dissolved in tetrahydrofuran (0.2M). The solution was cooled to -78 ° C under nitrogen and lithium diisopropylamine (1 eq.) Was added. After 10 minutes, methyl iodide (1 eq.) Was added and the temperature was warmed to 0 ° C and the reaction mixture was stirred for 30 minutes. The reaction mixture was then warmed to room temperature and quenched with water. The solvents were ent under reduced pressure followed by dilution with ethyl acetate and extraction with saturated ammonium chloride. The solvents were removed under reduced pressure to give the product as a colorless oil. EI-MS m / z 334 (M + H) ⁺ .

Step B: Methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) propanoate hydrochloride

Methyl 2- (2- (tert-butoxycarbonyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) propanoate was dissolved in 4 M HCl in dioxane (0.2 M). After 18 hours the solvent was removed under reduced pressure; subsequent trituration with ether gave the product. EI-MS m / z 233 (M + H) ⁺ .

Step C: Methyl 2- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H 5H-benzo [e] azapin-5-yl) propanoate

2- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e ] azapin-5-yl) propanoate was prepared from 3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) prop-1-ylamine and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) propanoate was prepared according to the method of Example 34. 3- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-yl) prop-1-ylamine was prepared according to Duggan, ME. WO 98/18640 produced. EI-MS m / z 451 (M + H) ⁺ .

Example 37

Preparation of 2- (2- (N- (3- (1,2,3,4-Tetrahydropyridino (2,3-b) pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) propanoic acid

2- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e ] azapin-5-yl) propanoic acid was prepared from methyl 2- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) propyl) carbamoyl) 1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) propanoate prepared according to the method of Example 34. EI-MS m / z 437 (M + H) ⁺ ; ¹ H-NMR (400 MHz, CDCl _3): δ 10.8 (br s, 1H), 7.25 (m, 6H), 6.37 (m, 1H), 5.04 (d, J = 14 , 2 Hz, 1H), 4.36 (d, J = 14.8 Hz, 1H), 3.74 (m, 5H), 3.46 (m, 4H), 3.10 (m, 3H), 2.72 (m, 5H), 2.27 (m, 1H), 1.44 (m, 1H), 1.17 (br s, 3H).

Example 38

Preparation of 2- (2- {N- [2,2-dimethyl-3- (2-pyridylamino) -propyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetic acid

Step A: (3-Amino-2,2-dimethylpropyl) -2-pyridylamine

A mixture of 2-fluoropyridine and 2,2-dimethyl-1,3-propanediamine (2 eq.) In pyridine (0.3 M) was refluxed for 18 hours and then concentrated by rotary evaporation. The solution was then concentrated under reduced pressure and the residue was partitioned between ethyl acetate and 10% sodium carbonate. The phases were separated and the organic phase was washed with brine dried, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash chromatography using 10: 1: 1 EtOH / NH ₄ OH / H ₂ O as eluent. EI-MS m / z 180 (M + H) ⁺ .

Step B: Methyl 2- (2- {N- [2,2-dimethyl-3- (2-pyridylamino) -propyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate

Methyl 2- (2- {N- [2,2-dimethyl-3- (2-pyridylamino) -propyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate was obtained (3-Amino-2,2-dimethylpropyl) -2-pyridylamine and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) propanoate were prepared according to the method of Example 34. EI-MS m / z 425 (M + H) ⁺ .

Step C: 2- (2- {N- [2,2-Dimethyl-3- (2-pyridylamino) -propyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] atepin-5-yl) acetic acid

2- (2- {N- [2,2-dimethyl-3- (2-pyridylamino) -propyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetic acid was prepared from methyl 2- (2- {N- [2,2-dimethyl-3- (2-pyridylamino) -propyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl according to the method of Example 34 EI-MS m / z 411 (M + H) ⁺ ; ¹ H-NMR (400 MHz, MeOH-d ₄ ): δ 7.8 (d, J = 5.1, 1H), 7.35 ( t, J = 7.12, 1H), 7.28 (d, J = 7.03, 1H), 7.10 (m, 2H), 7.00 (m, 1H), 6.5-6, 4 (m, 2H), 4.5 (q, J = 15.37 Hz, 2H), 3.6 (m, 2H), 3.45 (m, 1H), 3.25 (s, 3H), 2.9 (d, J = 8.67 Hz, 4H), 2.7-2.06 (m, 2H), 1.95 (m, 1H), 1.55 (m, 1H), 0.7 (s, 6H).

Example 39

Preparation of 2- (2- {N- [4- (pyrazine-2-ylamino) -butyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetic acid

Step A: (4-Aminobutyl) pyrazine-2-ylamine

(4-Aminobutyl) pyrazine-2-ylamine was prepared by refluxing 2-chloropyrazine and 1,4-diaminobutane in pyridine (50 ml) for 18 hours. The solution was then concentrated under reduced pressure and the residue was partitioned between ethyl acetate and 10% sodium carbonate. The phases were separated and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The desired product was isolated by flash chromatography using 10: 1: 1 ethanol / ammonium hydroxide / water. EI-MS m / z 167 (M + H) ⁺ .

Step B: Methyl 2- (2- {N- [2,2-dimethyl-3- (2-pyridylamino) -propyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate

Methyl 2- (2- {N- [2,2-dimethyl-3- (2-pyridylamino) -propyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate was obtained (4-aminobutyl) pyrazine-2-ylamine and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) propanoate prepared according to the method of Example 34. EI-MS m / z 412 (M + H) ⁺ .

Step C: 2- (2- {N- [4- (pyrazine-2-ylamino) -butyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetic acid

2- (2- {N- [4- (pyrazine-2-ylamino) -butyl] -carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetic acid was prepared from methyl 2- (2 - {N- [2,2-dimethyl-3- (2-pyridylamino) -propyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate prepared according to the method of Example 34.
EI-MS m / z 398 (M + H) ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.9 (m, 1H), 7.88 (s, 1H), 7.6 (s, 1H), 7.30 (d, 7, 2, 1H), 7.18-7.08 (m, 3H), 6.95 (t, J = 5.01, 1H), 6.3 (t, J = 5.15, 1H), 4, 45 (s, 2H), 3.5 (sb, 2H), 3.15 (m, 3H), 2.95 (m, 2H), 2.20-2.10 (m, 2H), 1.8 (m, 1H), 1.4 (m, 5H).

Example 40

Preparation of 2- {2- (N- (3-Imidazolo [5,4-b] pyridin-2-yl-propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid

Step A: N- (3-Amino (2-pyridyl)) - 4 - [(phenylmethoxy) carbonylamino] butanamide

4 - [(phenylmethoxy) carbonylamino] butanoic acid (1.1 eq.) Was dissolved in methylene chloride (0.2 M), followed by the addition of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDCA ) (1.2 eq.) And triethylamine (1.5 eq.). The mixture was stirred under nitrogen for 30 minutes at room temperature, followed by the addition of 2,3-diaminopyridine. The mixture was then stirred at room temperature for 48 hours, quenched with saturated ammonium carbonate and extracted with ether. The organic phase was concentrated under reduced pressure and chromatographed on silica gel (10% MeOH / CH ₂ Cl ₂ ).
EI-MS m / z 329 (M + H) ⁺ .

Step B: N- (3-Imidazolo [4,5-b] pyridin-2-yl-propyl) (phenylmethoxy) carboxamide

N- (3-Amino (2-pyridyl)) - 4 - [(phenylmethoxy) carbonylamino] butanamide was dissolved in acetic acid (0.3 M) and heated at reflux for 18 hours. The resulting mixture was basified with saturated sodium carbonate, extracted with methylene chloride, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (10% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 311 (M + H) ⁺ .

Step C: 3-Imidazolo [4,5-b] pyridin-2-yl-propylamine

N- (3-Imidazolo [4,5-b] pyridin-2-yl-propyl) (phenylmethoxy) carboxamide was dissolved in MeOH (60 ml) and 10% Pd / C was added. Hydrogen was bubbled through the mixture and stirred under a balloon atmosphere for 18 hours. The mixture was filtered through celite and concentrated by high vacuum to give the desired product.
EI-MS m / z 177 (M + H) ⁺ .

Step D: Methyl 2- {2- [N- (3-imidazolo [5,4-b] pyridin-2-yl-propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepine-5 yl} acetate

Methyl 2- {2- [N- (3-imidazolo [5,4-b] pyridin-2-yl-propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} Acetate was prepared from 3-imidazolo [4,5-b] pyridin-2-yl-propylamine and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) -propanoate according to the method of Example 34 produced. EI-MS m / z 422 (M + H) ⁺ .

Step E: 2- {2- [N- (3-Imidazolo [5,4-b] pyridin-2-yl-propyl) carbamoyl] 1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetic acid

2- {2- [N- (3-Imidazolo [5,4-b] pyridin-2-yl-propyl) carbamoyl] 1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid was prepared from methyl 2- {2- [N- (3-Imidazolo [5,4-b] pyridin-2-yl-propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate according to prepared by the method of Example 34.
EI-MS m / z 408 (M + H) ⁺ .

Example 41

Preparation of 2- {2- [N- (methylethyl) -N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] -1H, 3H , 4H, 5H-benzo [e] azepin-5-yl} acetic acid

Step A: Methyl 2- {2- [N- (methylethyl) -N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] - 1H,3H, 4H,5H-benzo [e] azepin-5-yl} acetate

Methyl 2- {2- [N- (methylethyl) -N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] -1H, 3H , 4H, 5H-Benzo [e] azepin-5-yl} acetate was prepared from (methylethyl) (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) amine and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) propanoate according to the method of Example 34. EI-MS m / z 465 (M + H) ⁺ .

Step B: 2- {2- [N- (Methylethyl) -N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid

2- {2- [N- (methylethyl) -N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] -1H, 3H, 4H , 5H-Benzo [e] azepin-5-yl) acetic acid was prepared from methyl 2- {2- [N- (methylethyl) -N- (2- (1,2,3,4-tetrahydropyridino [2,3- b] pyridin-7-yl) ethyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate was prepared according to the method of Example 34. EI-MS m / z 451 (M + H) ⁺ .
¹ H-NMR (400 MHz, CDCl _3): δ 10.0 bs, 1H), 7.25-7.10 (m, 6H), 6.25 (d, J = 7.27, 1H), 4 , 5 (q, J = 15.30, 2H), 3.7-3.6 (m, 2H), 3.4 (m, 5H), 3.23-3.15 (m, 1H), 2 , 78-2.65 (m, 5H), 2.65-2.55 (m, 1H), 2.2 (m, 1H), 1.88 (m, 2H), 1.78 (m, 1H ), 1.05 (dd, J = 6.7, J = 10.23, 6H).

Example 42

Preparation of 2- (2-aza-2-cyano-1 ((1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) amino) vinyl) -1H, 3H, 4H , 5H-benzo [e] azapin-5-yl) acetic acid

Step A: 2-Aza-3-phenoxy-3 - ((3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) amino) prop-2-enenitrile

2-Aza-3-phenoxy-3 - ((3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) -propyl) -amino) -prop-2-enenitrile was prepared from (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-yl) prop-1-ylamine and 2-aza-3,3-diphenoxyprop-2-enenitrile by heating in acetonitrile under 3 hours Reflux produced. 3- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-yl) prop-1-ylamine was prepared according to Duggan, ME. WO 98/18460 produced.

Step B: Methyl 2- (2-aza-2-cyano-1 - ((3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) amino) vinyl ) -1H,3H, 4H, 5H-benzo [e] azepin-5-yl) acetate

Methyl-2- (2-aza-2-cyano-1 - ((3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) amino) vinyl) -1H , 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate was prepared from 2-aza-3-phenoxy-3 - ((3- (1,2,3,4-tetrahydropyridino [2,3-b ] pyridin-7-yl) propyl) amino) prop-2-enenitrile and methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate by heating in isopropyl alcohol for 18 hours prepared under reflux, followed by flash chromatography (10% MeOH / CH ₂ Cl ₂ .

Step C: 2- (2-Aza-2-cyano-1 - ((1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) amino) vinyl) -1H, 3H , 4H, 5H-benzo [e] azapin-5-yl) acetic acid

2- (2-aza-2-cyano-1 - ((1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) amino) vinyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid was prepared from methyl 2- (2-aza-2-cyano-1 - ((3- (1,2,3,4-tetrahydropyridino [2,3-b ] pyridin-7-yl) propyl) amino) vinyl) -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate prepared according to the method of Example 34. EI-MS m / z 447 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.50-7.25 (m, 5H), 7.18 (d, J = 7.3 Hz, 1H), 6.34 (d, J = 7.2 Hz, 1H), 4.81 (q, J = 36 Hz, 2H), 3.82 (m, 2H), 3.65-3.48 (m, 5H), 3.40 (t , J = 5.3 Hz, 2H), 2.76 (t, J = 6.1 Hz, 2H), 2.70 (m, 2H), 2.11 (m, 1H), 1.92 (m , 4H), 1.70 (m, 1H).

Example 43

Preparation of 2- (2- (N - ((benzylamino) carbonylamino) phenyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

Step A: Methyl 2- (2- (N- (4-nitrophenyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate

Methyl 2- (2- (N- (4-nitrophenyl) carbamoyl) 1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate was prepared by reacting 4-nitrophenyl isocyanate and methyl-2 for 18 hours - (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate prepared in dimethylformamide at 60 ° C, followed by flash chromatography (10% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 384 (M + H) ⁺ .

Step B: Methyl 2- (2- (N- (4-aminophenyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate

Methyl 2- (2- (N- (4-aminophenyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate was obtained by hydrogenating methyl 2- (2- (N - (4-nitrophenyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate with Pd / C in methanol. EI-MS m / z 354 (M + H) ⁺ .

Step C: Methyl 2- (2- (N - ((benzylamino) carbonylamino) phenyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate

Methyl 2- (2- (N - ((benzylamino) carbonylamino) phenyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaδ pin-5-yl) acetate was prepared by heating methylene chloride for 18 h. 2- (2- (N- (4-aminophenyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate and benzyl isocyanate prepared in dimethylformamide at 60 ° C followed by flash chromatography. Chromatography (10% MeOH / CH ₂ Cl ₂ ).
EI-MS m / z 487 (M + H) ⁺ .

Step D: 2- (2- (N - ((Benzylamino) carbonylamino) phenyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

2- (2- (N - ((Benzylamino) carbonylamino) phenyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid was prepared from methyl 2- (2- (N- ((benzylamino) carbonylamino) phenyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate was prepared according to the method of Example 34.
EI-MS m / z 473 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 8.22 (s, 1H), 8.09 (s, 1H), 7.25-6.95 (m, 13H), 6.39 (t , J = 6.0 Hz, 1H), 4.52 (q, J = 35 Hz, 2H), 4.12 (d, J = 5.3 Hz, 2H), 3.55 (m, 2H), 3.38 (m, 1H), 2.61 (m, 2H), 1.81 (m, 1H), 1.47 (m, 1H).

Example 44

Preparation of 2- (2- (N- (3- (2-pyridylamino) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

Step A: (tert-butoxy) -N- (6-methyl (2-pyridyl)) carboxamide

To a stirred solution of 2-amino-6-methylpyridine in methylene chloride (1.0 M) was added di-tert-butyl dicarbonate (1 eq.) And the solution was stirred for 4 hours. The solution was then concentrated under reduced pressure and the residue was purified by flash chromatography (50% EtOAc / hexane). (EI-MS m / z 209 (M + H) ⁺ .

Step B: (tert-butoxy) -N- (6-but-3-enyl (2-pyridyl)) carboxamide

To a stirred solution of (tert-butoxy) -N- (6-methyl (2-pyridyl)) carboxamide in tetrahydrofuran (0.1 M) was added n-butyllithium (2.1 eq.) At -78 ° C. and the solution was warmed to 25 ° C and stirred for 1 hour. The solution was then cooled again to -78 ° C followed by the addition of allyl bromide (1.5 eq.) And continued stirring for 1 hour. The reaction was quenched with saturated ammonium chloride, diluted with ethyl acetate and separated. The organic layer was washed with brine and dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (5% EtOAc / hexane). EI-MS m / z 249 (M + H) ⁺ .

Step C: N- [6- (3,4-Dihydroxybutyl) (2-pyridyl)] (tert-butoxy) carboxamide

To a stirred solution of 4-methylmorpholine N-oxide (2.1 eq.) And osmium tetroxide (2.5 eq.) In tetrahydrofuran / water (5 eq / 1 eq.) Was added (tert-butoxy) -N- (6-but-3-enyl (2-pyridyl)) carboxamide (1.0 eq.) Was added at 25 ° C and stirred for 18 hours. The reaction was quenched with a solution of sodium bisulfate (0.5 M) and sodium sulfite (1 M) and stirred for 30 minutes. The reaction mixture was poured into brine and extracted with ethyl acetate. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (50% EtOAc / hexane). EI-MS m / z 283 (M + H) ⁺ .

Step D: (tert-butoxy) -N- [6- (3-oxopropyl) (2-pyridyl)] carboxamide

To a stirred solution of N- [6- (3,4-dihydroxybutyl) (2-pyridyl)] (tert-butoxy) carboxamide in tetrahydrofuran / water (1 eq / 1 eq, 0.1 M) was added sodium metaperiodate ( 1.3 eq.) At 0 ° C and stirred for 1 hour. The reaction mixture was warmed to room temperature and diluted with ethyl acetate. The reaction mixture was extracted with saturated sodium bicarbonate, dried with sodium sulfate, filtered and concentrated under reduced pressure to give the product. EI-MS m / z 251 (M + H) ⁺ .

Step E: (tert-butoxy) -N- [6- (3-hydroxyimino) propyl) (2-pyridyl)] carboxamide

To a stirred solution of (tert-butoxy) -N- [6- (3-oxopropyl) (2-pyridyl)] carboxamide in methanol (0.1 M) was added sodium acetate (2.0 eq.) And hydroxylamine hydrochloride , The reaction mixture was then warmed to 60 ° C and stirred for 18 hours. The reaction mixture was cooled to room temperature and diluted with water. The reaction mixture was extracted with diethyl ether. The organic layer was washed with saturated sodium bicarbonate and brine and dried with sodium sulfate, filtered and concentrated under reduced pressure to give the product. EI-MS m / z 266 (M + H) ⁺ .

Step F: N- [6- (3-Aminopropyl) (2-pyridyl)] (tert-butoxy) carboxamide

To a solution of (tert-butoxy) -N- [6- (3- (hydroxyimino) propyl) (2-pyridyl)] carboxamide in ethanol / acetic acid (4 eq / 1 eq, 0.1 M) under nitrogen 5% palladium on carbon was added. The reaction mixture was stirred under nitrogen for 18 hours at 60 psi. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give the product. EI-MS m / z 252 (M + H) ⁺ .

Step G: Methyl 2- {2- [N- (3- {6 - [(tert-butoxy) carbonylamino] -2-pyridyl} propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepine -5-yl} acetate

Methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate hydrochloride was dissolved in methylene chloride and washed with 1N NaOH. The organic layer was separated, dried over sodium sulfate and concentrated by rotary evaporation. The residue was stirred under nitrogen with 20% phosgene in toluene (0.1 M) for 10 minutes. After concentration by rotary evaporation, the residue was dissolved in THF (0.1 M), followed by the addition of diisopropylethylamine (1.5 eq.) And N- [6- (3-aminopropyl) (2-pyridyl)] (tert -butoxy) carboxamide (1.2 eq.). The reaction mixture was stirred under nitrogen for 18 hours, followed by rotary evaporation, and the product was purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 497 (M + H) ⁺ .

Step H: Methyl 2- (2- {N- [3- (6-amino-2-pyridyl) -propyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate

Methyl 2- {2- [N- (3- {6 - [(tert-butoxy) carbonylamino] -2-pyridyl} propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5- yl} acetate was dissolved in 4 M HCl / dioxane and stirred for 3 hours at room temperature. The reaction mixture was concentrated by rotary evaporation and the product was purified by trituration with diethyl ether. EI-MS m / z 397 (M + H) ⁺ .

Step 1: Methyl 2- {2- [N- (3- {6- [benzylamino] -2-pyridyl} propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate

To a stirred solution of methyl 2- (2- {N- [3- (6-amino-2-pyridyl) -propyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate in dichloroethane (0.4 M) at RT under nitrogen were added benzaldehyde (1.2 eq.), sodium triacetoxyborohydride (2 eq.) and acetic acid (4 eq.). After 5 hours, the reaction was quenched carefully with 2M sodium carbonate and extracted with methylene chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (10% MeOH / CH ₂ Cl ₂ ) to give the product. EI-MS m / z 487 (M + H) ⁺ .

Step J: 2- (2- [N- (3- [6- (Benzylamino] -2-pyridyl} propyl) carbamoyl] 1H, 3H, 4H, 4H-benzo [e] azepin-5-yl} acetic acid

To a stirred solution of methyl 2- {2- [N- (3- {6- [benzylamino] -2-pyridyl} propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepine-5 yl} acetate in methanol (0.1 M) was added 1 N NaOH (3 eq.). After 18 hours, the reaction mixture was neutralized with 10% HCl, concentrated under reduced pressure and purified by recrystallization from 2% MeOH / CH ₂ Cl ₂ . EI-MS m / z 473 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d ₂ -D ₂ O): δ 7.32-7.08 (m, 10H), 6.48 (m, 2H), 4.37 (s, 2H), 4.51 (m, 2H), 4.36 (m, 3H), 3.99 (t, J = 3.7Hz, 2H), 2.61-2.34 (m, 5H), 1.75 (m, 1H), 1.63 (t, J = 3.4 Hz, 2H).

Example 45

Preparation of 2- (2 - (((2- (1,2,3,4-Tetrahydropyridino (2,3-b) pyridin-7-yl) ethyl) amino) sulfonyl) -1H, 3H, 4H, 5H- benzo [e] azapin-5-yl) acetic acid

2- (2- (N- (2- (1,2,3,4-tetrahydro pyridino (2,3-b) pyridin-7-ylethyl) amino) sulfonyl) 1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid was prepared from 3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethylamine and methyl 2- (1H, 2H, 3H, 4H, 5H benzo [a] azaperhydroepin-5-yl) acetate prepared according to the method of Example 14. 2- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-yl) ethylamine was prepared according to Duggan, ME, WO 98/18460 produced. EI-MS m / z 445 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.11-6.87 (m, 5H), 6.10 (m, 1H), 4.21 (q, J = 48.6 Hz, 2H ), 3.50-3.29 (m, 3H), 3.11 (m, 2H), 2.80 (m, 2H), 2.55-2.44 (m, 4H), 2.19 ( m, 2H), 1.80 (m, 1H), 1.68 (m, 2H), 1.45 (m, 1H).

Example 46 (reference)

Preparation of methyl 3- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) propanoate hydrochloride

Step A: tert -Butyl-5- (2-hydroxyethyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepine-2-carboxylate

tert-Butyl-5- (2-hydroxyethyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepine-2-carboxylate was prepared by reacting methyl 2- (2- (tert-butoxycarbonyl) for 1.5 hours. 1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate with diisobutylaluminum hydride (3 eq.) In toluene (0.1M) at 0 ° C. The reaction was quenched with 1N HCl at 0 ° C and extracted with ethyl acetate. The organic layer was washed with additional 1N HCl, saturated sodium bicarbonate and water, dried with sodium sulfate, filtered and concentrated under reduced pressure to give the product. EI-MS m / z 292 (M + H) ⁺ .

Step B: tert -Butyl 5- (2 (4-methylphenyl) sulfonyloxy) 1H, 3H, 4H, 5H-benzo [e] azaperhydroepine-2-carboxylate

tert -Butyl 5- (2 ((4-methylphenyl) sulfonyloxy) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepine-2-carboxylate was prepared by stirring tert-butyl-5- (2- hydroxyethyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepine-2-carboxylate with tosyl chloride (1.1 eq.) and triethylamine (1.5 eq.) in methylene chloride at 25 ° C, diluted with methylene chloride, extracted with water, dried with sodium sulfate, filtered and concentrated under reduced pressure, flash chromatography (25% EtOAc / Hex) gave the product, EI-MS m / z 446 (M + H) ⁺ .

Step C: tert -Butyl-5- (2-cyanoethyl) -1H.3H, 4H, 5H-benzo [e] azaperhydroepine-2-carboxylate

tert -Butyl 5- (2-cyanoethyl) 1H, 3H, 4H, 5H-benzo [e] azaperhydroepine-2-carboxylate was prepared by stirring tert-butyl 5- (2 ((4-methylphenyl) sulfonyloxy for 18 hours ) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepine-2-carboxylate in dimethylsulfoxide (0.1M) with sodium cyanide (5 eq.) At 25 ° C, diluted with ethyl acetate, extracted with water, with sodium sulfate dried, filtered and concentrated under reduced pressure to give the product EI-MS m / z 323 (M + Na) ⁺ .

Step D: Methyl 3- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) propanoate hydrochloride

Methyl 3- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) propanoate hydrochloride was prepared by stirring tert-butyl-5- (2-cyanoethyl) -1H, 3H for 24 hours , 4H, 5H-benzo [e] azaperhydroepine-2-carboxylate in methanol with the addition of excess 4M HCl / dioxane and concentrated under reduced pressure to give the product. EI-MS m / z 234 (M + H) ⁺ .

Example 47

Preparation of 3- (2- (N- (2- (1,2,3,4-Tetrahydropyridino (2,3-b) pyridin-7-yl) ethyl) amino) sulfonyl) -1H, 3H, 4H, 5H -benzo [e] azapin-5-yl) propanoic acid

3- (2- (N- (2- (1,2,3,4-tetrahydro pyridino (2,3-b) pyridin-7-yl) ethyl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) propanoic acid was prepared from 3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethylamine and methyl 3- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) propanoate was prepared according to the method of Example 14. 2- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-yl) ethylsilamine was prepared according to Duggan, ME, WO 98/18460 produced. EI-MS m / z 459 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.39 (m, 1H), 7.30 (m, 3H), 7.18 (d, J = 7.2 Hz, 1H), 6, 35 (d, J = 7.3 Hz, 1H), 4.50 (m, 2H), 3.58 (m, 2H), 3.38 (t, J = 5.4 Hz, 2H), 3, 08 (m, 3H), 2.69 (m, 4H), 2.40 (m, 2H), 2.21 (m, 1H), 2.10 (m, 2H), 1.92 (m, 2H ), 1.80 (m, 1H).

Example 48 (reference)

Preparation of 5- (1H-1,2,3,4-tetraazol-5-ylmethyl) -1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepine-2-carboxylate

Step A: 3 - (((2-Bromophenol) methylamino) propan-1-ol

To a stirred solution of 2-bromobenzaldehyde in dichloroethane (0.4 M) at RT under nitrogen was added 3-aminopropanol (1.5 eq.), Sodium triacetoxyborohydride (2 eq.) And acetic acid (4 eq.). After 5 hours, the reaction was quenched carefully with 2M sodium carbonate and extracted with methylene chloride. The organic phase was extracted with 1N hydrochloric acid. The aqueous phase was neutralized with 1N sodium hydroxide and extracted with methylene chloride. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product.
EI-MS m / z 245 (M + H) ⁺ .

Step B: (tert-butoxy) -N - ((2-bromophenyl) methyl) -N- (3-hydroxypropyl) carboxamide

To a stirred solution of 3 - (((2-bromophenyl) methyl) amino) propan-1-ol in methylene chloride (0.1 M) was added di-tert-butyl dicarbonate (1.1 eq.). After 1 hour, the solvent was removed by rotary evaporation and the residue was partitioned between ether and 1N HCl. The ether portion was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product. EI-MS m / z 344 (M + H) ⁺ .

Step C: N - ((3E) -4-cyanobut-3-enyl (tert -butoxy) -N - ((2-bromophenyl) methyl) carboxamide

To a stirred solution of dimethyl sulfoxide (3.8 eq.) In methylene chloride (0.1 M) at -78 ° C was added oxalyl chloride (1.8 eq.). After 10 minutes, (tert-butoxy) -N - ((2-bromophenyl) methyl) -N- (3-hydroxypropyl) carboxamide (1 eq.) Was added. After stirring for 30 minutes, diisopropylethylamine (4 eq.) Was added and the reaction mixture was allowed to warm to rt. After 30 minutes, (triphenylphosphoranylidene) acetonitrile (1.2 eq.) Was added and stirring was continued for 18 hours. The mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product. EI-MS m / z 365 (M + H) ⁺ .

Step D: tert -butyl-5- (cyanomethylene) -1H, 3H, 4H-benzo [e] azaperhydroepine-2-carboxylate

To a stirred solution of N - ((3E) -4-cyanobut-3-enyl (tert-butoxy) -N - ((2-bromophenyl) methyl) carboxamide in acetonitrile (0.1 M) was added triethylamine (1.2 Eq.), Palladium acetate (0.05 eq.), And tri-o-tolylphosphine (0.01 eq.) The reaction mixture was refluxed under nitrogen for 18 h and cooled to rt The solvent was removed by rotary evaporation, and the product was purified by flash chromatography (25% EtOAc / hexane) EI-MS m / z (MH) ^- .

Step E: tert -butyl-5- (cyanomethyl) -1H, 3H, 4H-benzo [e] azaperhydroepine-2-carboxylate

To a stirred solution of tert -butyl-5- (cyanomethylene) -1H, 3H, 4H-benzo [e] azaperhydroepine-2-carboxylate in methanol (0.1M) was added magnesium turnings (10 eq.) And the mixture was refluxed for 18 hours. The mixture was filtered through celite and concentrated by rotary evaporation. The product was purified by flash chromatography (25% EtOAc / hexane). EI-MS m / z 287 (M + H) ⁺ .

Step F: tert -Butyl-5- (1H-1,2,3,4-tetraazol-5-ylmethyl) -1H, 3H, 4H-benzo [e] azaperhydroepine-2-carboxylate

tert -Butyl 5- (1H-1,2,3,4-tetraazol-5-ylmethyl) -1H, 3H, 4H-benzo [e] azaperhydroepine-2-carboxylate was prepared by reacting tert-butyl alcohol for 48 hours. 5- (cyanomethyl) -1H, 3H, 4H-benzo [e] azaperhydroepine-2-carboxylate with sodium azide (1.8 eq.) And trimethyltin chloride in toluene at reflux. The solvent was evaporated to dryness. diluted with methylene chloride (100 ml) and extracted with 1N HCl. The solvent was evaporated and the product was purified by flash chromatography (10% MeOH / CH ₂ Cl ₂ ).
EI-MS m / z 328 (MH) ^- .

Step G: 5- (1H-1,2,3,4-Tetrazol-5-ylmethyl) -1H, 2H, 3H, 4H-benzo [e] azaperhydroepine-2-carboxylate hydrochloride

tert -Butyl 5- (1H-1,2,3,4-tetraazol-5-ylmethyl) -1H, 3H, 4H-benzo [e] azaperhydroepine-2-carboxylate was dissolved in 4M HCl in dioxane (0.2 M) dissolved. After 18 hours, the solvent was removed under reduced pressure, followed by trituration with ether to give the product. EI-MS m / z 230 (M + H) ⁺ .

Example 49

Preparation of [5- (1H-1,2,3,4-tetraazol-5-ylmethyl)] 1H, 3H, 4H, 5H-benzo [e] azepin-2-yl)] - N- (3- (1 propylcarboxamide, 2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl)

[5- (1H-1,2,3,4-tetraazole-5-ylmethyl)) 1H, 3H, 4H, 5H-benzo [e] azepin-2-yl)] - N- (1,2,3, 4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carboxamide was prepared from 3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) prop-1-ylamine and 5- (1H-1,2 , 3,4-tetraazol-5-ylmethyl) -1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepine-2-carboxylate prepared according to the method of Example 34. 3- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-yl) prop-1-ylamine was prepared according to Duggan, ME. WO 98/18460 produced. EI-MS m / z 447 (M + H) ⁺ .

Example 50 (reference)

Preparation of methyl 2 - ((5S) -1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate hydrochloride

Step A: Methyl 2 - ((5S) -2- (tert-butoxycarbonyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate was prepared according to the method of Example 34. The product was separated and purified by reverse phase high pressure liquid chromatography (2% EtOH / hexane) on a Chiralpak AD column (250 x 4.6 mm I.D.) at room temperature at a flow rate of 1.0 ml / min. EI-MS m / z 318 (M + H) ⁺ .

Step B: Methyl 2 - ((5S) -1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate hydrochloride

(+) Methyl 2 - ((5S) -2- (tert-butoxycarbonyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate was dissolved in 4M HCl in dioxane (0.2 M) dissolved. After 18 hours, the solvent was removed under reduced pressure, followed by trituration with ether to give the product. EI-MS m / z 220 (M + H) ⁺ , optical rotation: + 0.104 °.

Example 51 (reference)

Preparation of methyl 2 - ((5R) -1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate hydrochloride

Step A: Methyl 2 - ((5R) -2- (tert-butoxycarbonyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate was prepared according to the method of Example 34. The product was separated and purified by reverse phase high pressure liquid chromatography (2% EtOH / hexane) on a Chiralpak AD column (250 x 4.6 mm I.D.) at room temperature at a flow rate of 1.0 ml / min. EI-MS m / z 318 (M + H) ⁺ .

Step F: Methyl 2 - ((5R) -1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate hydrochloride

(-) Methyl 2 - ((5R) -2- (tert-butoxycarbonyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

was dissolved in 4 M HCl in dioxane (0.2 M). After 18 hours, the solvent was removed under reduced pressure followed by trituration with ether to give the product.
EI-MS m / z 220 (M + H) ⁺ , optical rotation: -0.113 °.

Example 52

Preparation of 2 - ((5R) -2- (N- (3- (1,2,3,4-Tetrahydropyridino (2,3-b) pyridin-7-yl) prop-1-yl) carbamoyl) -1H , 3H, 4H,5H-benzo [e] azapin-5-yl) acetic acid

2 - ((5R) -2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) prop-1-yl) carbamoyl) -1H,3H , 4H, 5H-Benzo [e] azapin-5-yl) acetic acid was prepared from 3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) prop-1-ylamine and methyl -2 - ((5R) -1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate was prepared according to the method of Example 34. 3- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-yl) prop-1-ylamine was prepared according to Duggan, ME. WO 98/18460 produced. EI-MS m / z 423 (m + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.30-6.85 (m, 5H), 6.25 (m, 1H), 6.18 (d, J = 7.3 Hz, 1H ), 4.41 (q, J = 37.5 Hz, 2H), 3.59 (m, 1H), 3.40 (m, 2H), 3.28 (m, 2H), 2.95 (m , 2H), 2.60 (t, J = 6.0 Hz, 2H), 2.31 (m, 4H), 1.77 (m, 3H), 1.61 (t, J = 7.4 Hz , 2H), 1.40 (m, 1H).

Example 53

Preparation of 2 - ((5R) -2- (N- (3- (1,2,3,4-Tetrahydropyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H , 5H-benzo [e] azapin-5-yl) acetic acid

2 - ((5R) -2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H, 5H benzo [e] azapin-5-yl) acetic acid was prepared from 3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethylamine and methyl 2 - ((5R) - 1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate prepared according to the method of Example 34. 3- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-yl) ethylamine was prepared according to Duggan, ME. WO 98/18460 produced.
EI-MS m / z 409 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.30-6.94 (m, 5H), 6.41 (bs, 1H), 6.30 (s, 1H), 6.20 (i.e. , J = 7.2 Hz, 1H), 4.47 (q, J = 38 Hz, 2H), 3.60 (m, 1H), 3.45 (m, 2H), 3.23-3.20 (m, 5H), 2.60 (m, 2H), 2.30 (m, 2H), 1.74 (m, 3H), 1.40 (m, 2H).

Example 54

Preparation of 2 - ((5S) -2- (N- (3- (1,2,3,4-Tetrahydropyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H , 5H-benzo [e] azapin-5-yl) acetic acid

2 - ((5S) -2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H, 5H -ben zo [e] azapin-5-yl) acetic acid was prepared from 3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethylamine and methyl 2 - ((5S) -1H , 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate, prepared according to the method of Example 34. 3- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-yl) ethylamine was prepared according to Duggan, ME. WO 98/18460 produced. EI-MS m / z 409 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.30-6.95 (m, 5H), 6.38 (bs, 1H), 6.29 (s, 1H), 6.20 (i.e. , J = 6.8 Hz, 1H), 4.48 (q, J = 38.6 Hz, 2H), 3.60 (m, 1H), 3.45 (m, 2H), 3.28-3 , 22 (m, 5H), 2.61 (m, 2H), 2.34 (m, 2H), 1.80 (m, 3H), 1.46 (m, 2H).

Example 55

Preparation of 2 - ((5S) -2- (4- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) butanoyl) carbamoyl) -1H, 3H, 4H, 5H- benzo [e] azapin-5-yl) acetic acid

2-Methyl - ((5S) -2- (4- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) butanoyl) carbamoyl) -1H, 3H, 4H, 5H- Benzo [e] azapin-5-yl) acetic acid was prepared from 3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) butyric acid and methyl 2 - ((5S) -1H , 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate by stirring the two compounds in acetonitrile (0.1 M) with triethylamine (1.1 eq.) And 1- (3 eq Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.1 eq.) At room temperature. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography to give 2-methyl- ((5S) -2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridine -7-yl) prop-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate. 2 - ((5S) -2- (4- (1,2,3,4-tetrahydro pyridino (2,3-b) pyridin-7-yl) butanoyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [ e] azapin-5-yl) acetic acid was prepared according to Example 34. 3- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-yl) butyric acid was prepared according to Duggan, ME, WO 98/18460 produced. EI-MS m / z 406 (MH) ^- ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.27-6.97 (m, 5H), 6.21 (bs, 1H), 6.17 (m, 1H), 4.52 (q , J = 33.6 Hz, 2H), 3.80 (m, 1H), 3.56-3.45 (m, 2H), 3.30 (s, 2H), 2.94 (m, 2H) , 2.60 (m, 4H), 2.36 (m, 2H), 2.25 (m, 3H), 1.65 (m, 4H), 1.50 (m, 2H).

Example 56

Preparation of 2- [2- (4- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) butanoyl) -1H, 3H, 4H, 5H-benzo [e] azepine 5-yl] acetic acid

Step A: Methyl 2- [2- (4- {1 - [(tert-butyl) oxycarbonyl] -1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl} butanoyl) - 1H, 3H, 4H, 5H-benzo [e] azepin-5-yl] acetate

Methyl-2- [2- (4- {1 - [(tert-butyl) oxycarbonyl] -1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl} butanoyl) -1 H, 3 H 4H, 5H-benzo [e] azepin-5-yl] acetate was prepared according to the method of Example 55. EI-MS m / z 422 (M + H) ⁺ .

Step B: 2- [2- (4- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-yl) butanoyl) -1H, 3H, 4H, 5H-benzo [e] azepine -5-yl] acetic acid

To methyl 2- [2- (4- {1 - [(tert -butyl) oxycarbonyl] -1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl} butanoyl) -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl] acetate was added to 4.0M HCl / dioxane (4 ml) and the resulting mixture was stirred at room temperature for 18 hours, concentrated by rotary evaporation, diluted in MeOH, followed by the addition of 1N NaOH (5 eq.). The mixture was stirred at room temperature for 48 hours, acidified with 1N HCl, concentrated by rotary evaporation and extracted with dichloromethane. The organic solvent was concentrated under reduced pressure to give the desired product. EI-MS m / z 408 (M + H) ⁺ . ¹ H-NMR (400 MHz, CDCl _3): δ 7.3-7.1 (m, 4H), 6.35 (m, 2H), 4.75 (d, J = 15.1, 1H), 4.55 (m, 2H), 3.8 (m, 1H), 3.5 (m, 5H), 2.4 (m, 3H), 2.15 (m, 2H), 2.0 (m , 3H), 1.9 (m, 3H), 1.7 (m, 1H).

Example 57

Preparation of 2- (2 - ((5 - ((4,5-dichloroimidazolyl) methyl-2-furyl) carbonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

2- (2 - ((5 - ((4,5-dichloroimidazolyl) methyl-2-furyl) carbonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid was prepared from 5- (4,5-dichloroimidazolyl) methyl-2-furyl) carboxylic acid and methyl 2-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate by stirring the two compounds in acetonitrile for 18 hours (0.1M) with triethylamine (1.1 eq.) And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.1 eq.) At room temperature. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography to give methyl 2- (2 - ((5 - ((4,5-dichloroimidazolyl) methyl-2-furyl) carbonyl) -1H, 3H, 4H, 5H benzo [e] azapin-5-yl) acetate: 2- (2 - ((5 - ((4,5-dichloroimidazolyl) methyl-2-furyl) carbonyl) -1H, 3H, 4H, 5H-benzo. e] azapin-5-yl) acetic acid was prepared according to example 34. EI-MS m / z 449 (m + H) ^{+; 1} H-NMR (500 MHz, _CDCl3). δ 10.8 (br s, 1H ), 7.56 (m, 1H), 7.23 (m, 4H), 6.93 (m, 1H), 6.43 (m, 1H), 5.07 (m, 2H), 4.64 (m, 2H), 3.82 (m, 1H), 3.58 (m, 1H), 2.72 (m, 1H), 2.18 (m, 1H), 1.58 (m, 1H) ,

Example 58

Preparation of methyl 2- (2 - ((5 - ((benzylamino) carbonylamino) phenyl) -2-furyl) carbonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate

Methyl 2- (2 - ((5 - ((benzylamino) carbonylamino) phenyl) -2-furyl) carbonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate was prepared from 5- ((Benzylamino) carbonylamino) phenyl) -2-furyl) carboxylic acid and methyl 2-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate by stirring the two compounds in acetonitrile for 18 hours (0.1M) with triethylamine (1.1 eq.) And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.1 eq.) At room temperature. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography to give methyl 2- (2 - ((5 - ((benzylamino) carbonylamino) phenyl) -2-furyl) carbonyl) -1H, 3H, 4H, 5H- benzo [e] azapin-5-yl) acetate. EI-MS m / z 538 (M + H) ⁺ .

Example 59

Preparation of 2- (2 - ((5 - ((benzylamino) carbonylamino) phenyl) -2-furyl) carbonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

2- (2 - ((5 - ((Benzylamino) carbonylamino) phenyl) -2-furyl) carbonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid was prepared according to Example 34. EI-MS m / z 524 (M + H) ⁺ ; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 11.2 (br s, 1H), 8.00 (br s, 1H), 7.49 (m, 1H), 7.24 (m, 12H) , 6.48 (d, J = 3.3 Hz, 1H), 5.86 (m, 1H), 4.77 (m, 2H), 4.42 (m, 2H), 3.73 (m, 1H), 3.65 (m, 1H), 3.32 (m, 1H), 2.97 (m, 1H), 2.75 (m, 1H), 2.59 (m, 1H), 1, 50 (m, 1H).

Example 60

Preparation of 2- [3- (3- {N- [2- (2-pyridylamino) ethyl] carbamoyl) phenyl) -1H, 2H, 4H, 5H-benzo [d] azaperhydroepinyl] acetic acid

Step A: 2- (2-Bromophenol) -N- [3- (hydroxymethyl) phenyl] acetamide

To a stirred solution of 2- (2-bromophenyl) acetic acid in dichloromethane (0.2 M) was added (3-aminophenyl) methan-1-ol (1.2 eq.), Triethylamine (1.5 eq.) And EDAC (1.5 eq.) Was added. After 2 hours the solution was washed with water, 10% HCl, 10% sodium carbonate and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a colorless solid. EI-MS m / z 320/322 (M + H) ⁺ .

Step B: (3 - {[2- (2-Bromophenol) ethyl] amino} phenyl) methan-1-ol

2- (2-bromophenyl) -N- [3- (hydroxymethyl) phenyl] acetamide was dissolved in THF (0.2 M), followed by the addition of BH ₃ · DMS (3 eq.) And the reaction was Stirring heated to reflux. After 2 hours, the mixture was cooled to room temperature and quenched with an excess of 10% HCl. The mixture was refluxed for 1 hour and then cooled to room temperature. After washing with EtOAc, the aqueous phase was basified with 10% sodium carbonate and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with EtOAc to give a colorless solid. EI-MS m / z 307/309 (MxH) ⁺ .

Step C: Methyl (2E) -4 - {[2- (2-bromophenyl) ethyl] [3- (hydroxymethyl) phenyl] amino} but-2-enoate

(3 - {[2- (2-Bromophenyl) ethyl] amino} phenyl) methan-1-ol was dissolved in acetonitrile (0.2 M), followed by the addition of methyl 4-bromocrotonate (1.2 eq. and triethylamine (1.5 eq.), and the reaction mixture was refluxed for 18 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with 10% sodium carbonate, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (silica, 50% EtOAc / Hex) gave a colorless oil. EI-MS m / z 403/405 (M + H) ⁺ .

Step D: Methyl 2- {3- [3- (hydroxymethyl) phenyl] -2H, 4H, 5H-benzo [d] azaperhydroepinylidene} acetate

Methyl (2E) -4 - {[2- (2-bromophenyl) ethyl] [3- (hydroxymethyl) phenyl] amino) but-2-enoate was dissolved in toluene (0.1 M) followed by the addition of triethylamine (1 eq.), Tetrakis (triphenylphosphine) palladium (0.05 eq.) And 2 M sodium carbonate (15% by volume). The mixture was heated under vigorous stirring for 18 hours under reflux. After cooling to room temperature the phases were separated and the organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in EtOAc and extracted five times with 6N HCl. The combined extracts were neutralized with 10% sodium carbonate and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a yellow oil. EI-MS m / z 323 (M + H) ⁺ .

Step E: Methyl 2- {3- [3- (hydroxymethyl) phenyl] -1H, 2H, 4H, 5H-benzo [d] azaperhydroepinyl} acetate

Methyl 2- {3- [3- (hydroxymethyl) phenyl] -2H, 4H, 5H-benzo [d] azaperhydroepinyliden} acetate

was dissolved in MeOH (0.1 M) followed by the addition of magnesium turnings (10 eq.), and the mixture was refluxed for 18 hours. The mixture was filtered through celite and concentrated by rotary evaporation. The product was purified by flash chromatography (25% EtOAc / hexane). EI-MS m / z 325 (M + H) ⁺ .

Step F: Methyl 2- [3- (3-formylphenyl) -1H, 2H, 4H, 5H-benzo [d] azaperhydroepinyl] acetate

Methyl 2- {3- [3- (hydroxymethyl) phenyl] -1H, 2H, 4H, 5H-benzo [d] azaperhydroepinyl} acetate was dissolved in methylene chloride (0.1M) followed by addition of triethylamine (1M) Eq.), Dimethylsulfoxide (2 eq.) And sulfur trioxide-pyridine (1 eq.) And stirred for 5 hours. The mixture was filtered through celite and concentrated by rotary evaporation. The product was purified by flash chromatography (20% EtOAc / hexane). EI-MS m / z 323 (M + H) ⁺ .

Step G: Methyl 2- [3- (3- {N- [2- (2-pyridylamino) ethyl] carbamoyl} phenyl) -1H, 2H, 4H, 5H-benzo [d] azaperhydroepinyl] acetate

Methyl 2- [3- (3-formylphenyl) -1H, 2H, 4H, 5H-benzo [d] azaperhydroepinyl] acetate was dissolved in methylene chloride (0.4 M) at RT under nitrogen, followed by the addition of 2- (N- (2-aminoethyl) amino) pyridine (1.5 eq.), Sodium triacetoxyborohydride (2 eq.) And acetic acid (4 eq.). After 5 hours, the reaction was quenched carefully with 2M sodium carbonate and extracted with methylene chloride. The organic phase was extracted with 1 N hydrochloric acid. The aqueous phase was neutralized with 1N sodium hydroxide and extracted with methylene chloride. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product.
EI-MS m / z 445 (M + H) ⁺ .

Step H: 2- [3- (3- {N- [2- (2-Pyridylamino) carbamoyl} phenyl) -1H, 2H, 4H, 5H-benzo [d] azaperhydroepinyl] acetic acid

To a stirred solution of methyl 2- [3- (3- {N- [2- (2-pyridylamino) ethyl] carbamoyl} phenyl) -1H, 2H, 4H, 5H-benzo [d] azaperhydroepinyl] acetate in methanol (0.1 M) was added 1 N NaOH (3 eq.). After 18 hours, the reaction mixture was neutralized with 10% HCl, concentrated by rotary evaporation, and purified by recrystallization from 2% MeOH / CH ₂ Cl ₂ . EI-MS m / z 431 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d6-DMSO): δ 7.908 (d, J = 4.8 Hz, 1H), 7.33 (m, 2H); 7.21-7.04 (m, 3H), 6.83 (m, 1H), 6.61 (d, J = 7.3Hz, 1H), 6.49 (m, 2H), 3.86 (m, 2H), 3.75 (m, 2H), 3.35 (t, J = 3.5Hz), 3.05 (m, 1H), 2.93 (m, 3H), 2.40 (m, 2H), 2.25 (m, 1H), 2.09 (t, J = 3.5Hz, 1H).

Example 61

Preparation of 2- [3 - ({4 - [(Amidinoamino) methyl] phenyl} methyl) -1H, 2H, 4H, 5H-benzo [d] azepinyl] acetic acid

Step A: tert -Butyl (2Z) -2-aza-3 - [(tert-butoxy) carbonylamino] -3-methylthioprop-2-enoate

To a stirred solution of methylthiocarboxamidine in methylene chloride (0.2 M) was added di-tert-butyl dicarbonate (4 eq.) Followed by saturated sodium carbonate. After stirring for 18 hours, the reaction mixture was diluted with methylene chloride and separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (silica, 10% CHCl ₃ ) gave a colorless solid.
EI-MS m / z 291 (M + H) ⁺ .

Step B: tert -Butyl (2E) -3-amino-2-aza-3 - [(tert-butoxy) carbonylamino] prop-2-enoate

Tert-butyl (2Z) -2-aza-3 - [(tert-butoxy) carbonylamino] -3-methylthioprop-2-enoate was dissolved in MeOH (0.1 M) followed by the addition of 1N NH ₄ OH (5 eq.). After stirring overnight, the solution was concentrated under reduced pressure to give a colorless solid. EI-MS m / z 411 (M + H) ⁺ .

Step C: (tert-butoxy) -N - {[(tert-butoxy) carbonylaminoliminomethyl} -N - {[4- (bromomethyl) phenyl] methyl} carboxamide

tert -Butyl (2E) -3-amino-2-aza-3 - [(tert-butoxy) carbonylamino] prop-2-enoate was dissolved in dimethylformamide (0.1M) followed by the addition of NaH (1 eq.). After stirring for 5 minutes, α, α ^I -dibromo-p-xylene in dimethylformamide was added. The solution was stirred for 18 hours and then quenched with saturated ammonium chloride, diluted with ethyl acetate and washed with water and brine and dried with magnesium sulfate. The solution was concentrated under reduced pressure to give a colorless foam. EI-MS m / z 444 (M + H) ⁺ .

Step D: Methyl 2- [3 - ({4 - [((tert -butoxy) -N - {[(tert-butoxy) carbonylamino] iminomethyl} carbonylamino) methyl] phenyl} methyl) -1H, 2H, 4H, 5H-benzo [d] azepinyl] acetate

Methyl 2- (3- (phenylmethyl) -2H, 4H, 5H-benzo [d] azaperhydroepin-1-ylidene) acetate and (tert-butoxy) -N - {[(tert-butoxy) carbonylamino] iminomethyl} -N - {[4- (Bromomethyl) phenyl] methyl} carboxamide was dissolved in acetonitrile (0.1 M), followed by the addition of triethylamine (1 eq.). After stirring at 60 ° C for 18 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was extracted with 10% sodium bicarbonate, water and brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure to give a colorless foam. Flash chromatography (silica, 100% EtOAc) gave a colorless solid. EI-MS m / z 444 (M + H) ⁺ .

Step E: 2- [3- (4 - [((tert -butoxy) -N - {[carbonylamino] iminomethyl} carbonylamino) methyl] phenyl} methyl) -1H, 2H, 4H, 5H-benzo [d] azepinyl] acetic acid

To a stirred solution of methyl 2- [3 - ({4 - [((tert -butoxy) -N - {[(tert-butoxy) carbonylamino] iminomethyl} carbonylamino) methyl] phenyl} methyl) -1H, 2H, 4H, 5H-benzo [d] azepinyl] acetate in methanol (0.1M) was added 1N NaOH (3 eq). After 18 hours, the reaction mixture was neutralized with 10% HCl, concentrated by rotary evaporation, and purified by recrystallization from 2% MeOH / CH ₂ Cl ₂ . EI-MS m / z 466.

Step F: 2- [3 - ({4 - [(Amidinoamino) methyl] phenyl} methyl) -1H, 2H, 4H, 5H-benzo [d] azepinyl] acetic acid

2- [3 - ({4 - [((tert -butoxy) -N - {[carbonylamino] iminomethyl} carbonylamino) methyl] phenyl} methyl) -1H, 2H, 4H, 5H-benzo [d] azepinyl] acetic acid dissolved in 4 M HCl / dioxane and stirred for 3 hours at room temperature. The reaction mixture was concentrated by rotary evaporation and the product was purified by trituration with diethyl ether.
EI-MS m / z 366 (M + H) ⁺ ; (M + H) ⁺ ; ¹ H-NMR (400 MHz, d ₂ -D ₂ O): δ 7.40 (d, J = 8.0 Hz, 1H), 7.3 (d, J = 8.0 Hz, 2H), 7, 24-7.09 (m, 4H), 4.39 (s, 2H), 4.22 (q, J = 6.5 Hz, 2H), 3.70-3.60 (m, 2H), 3 , 48 (m, 1H), 3.24 (m, 2H), 3.01-2.78 (m, 2H), 2.71 (m, 1H).

Example 62 (reference)

Preparation of 2- (3- {N- [4- (Amidinoamino) -butyl] -carbamoyl} -1H,2H, 4H, 5H-benzo [d] azepinyl) acetic acid

Step A: tert -Butyl (2E) -3 - [(4-Aminobutyl) amino] -2-aza-3 - [(tert-butoxy) carbonylamino] prop-2-enoate

tert -Butyl (2Z) -2-aza-3 - [(tert-butoxy) carbonylamino] -3-methylthioprop-2-enoate was dissolved in MeOH (0.1M) followed by the addition of 1.4M. Diaminobutane (5 eq.). After stirring for 18 hours, the solution was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was separated and extracted with 10% HCl. The aqueous layer was neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography (10% MeOH / CH ₂ Cl ₂ ) gave the product. EI-MS 331 (M + H).

Step B: tert -Butyl (2E) -2-aza-3 - [(tert -butoxy) carbonylaminol-3 - {[4- ({1 - [(methoxycarbonyl) methyl] (1H, 2H, 4H, 5H- benzo [d] azepin-3-yl)} carbonylamino) butyl] amino} prop-2-enoate

Methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [d] azaperhydroepinyl) acetate hydrochloride was dissolved in methylene chloride and washed with 1N NaOH. The organic layer was separated, dried over sodium sulfate and concentrated by rotary evaporation. An excess of phosgene (20% in toluene) was added and the mixture was stirred for 5 minutes. The excess phosgene was gassed off and the residue was diluted with DMF (2.5 ml) under nitrogen. tert -butyl (2E) -3 - [(4-aminobutyl) amino] -2-aza-3 - [(tert -butoxy) carbonylamino] prop-2-enoate and triethylamine, previously dissolved in DMF (2 ml), were added to the mixture. The resulting mixture was stirred at room temperature for 18 hours, concentrated under high vacuum and chromatographed on silica gel using 10% MeOH / CHCl ₂ as eluent. EI-MS m / z 576 (M + H) ⁺ .

Step C: 2- (3- {N- [4-Amidinoamino) butyl] carbamoyl} -1H, 2H, 4H, 5H-benzo [d] azepinyl) acetic acid

tert-butyl (2E) -2-aza-3 - [(tert-butoxy) carbonylamino] -3 - {[4 - ({1 - [((methoxycarbonyl) methyl] 1H, 2H, 4H, 5H-benzo [ d] azepin-3-yl)} carbonylamino) butyl] amino} prop-2-enoate was dissolved in ethanol (40 ml), followed by the addition of 1N NaOH (7 ml). The mixture was stirred at room temperature overnight, acidified with 1N HCl and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, concentrated under high vacuum and chromatographed on silica gel using 5% MeOH / CH ₂ Cl ₂ as eluent. The resulting product was dissolved in 4.0 M HCl / dioxane, stirred for 18 hours, concentrated by rotary evaporation, and the resulting residue was redissolved in acetonitrile to remove excess HCl, to give the desired product. EI-MS m / z 396 (MH) ^- . ¹ H-NMR (400 MHz, MeOH-d ₄ ): δ 7.80 (s, 1H), 7.00 (m, 4H), 3.82-3.6 (m, 2H), 3.5 ( s, 1H), 3.45-3.31 (m, 2H), 3.10 (m, 5H), 2.80-2.5 (m, 3H), 1.5-1.35 (m, 5H).

Example 63

Preparation of 2-2- [N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetic acid

Step A: 2- (4-Bromophenyl) ethanenitrile

To a stirred solution of 2-bromobenzyl bromide in dimethyl sulfoxide (1.0 M) was added sodium cyanide (2 eq.) And the solution was stirred for 18 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic phase was washed with 10% HCl and brine and dried with magnesium sulfate. The solution was concentrated under reduced pressure to give the product. EI-MS m / z 196, 198 (M + H) ⁺ .

Step B: 2- (4-Bromophenol) -1- (hydroxyimino) ethylamine

To a stirred solution of 2- (4-bromophenyl) ethanenitrile in methanol / water (1 eq / 1 eq, 0.1 M) was added hydroxylamine hydrochloride (2.1 eq.) And sodium carbonate (2.0 eq. ) was added. The reaction mixture was stirred at 60 ° C for 5 hours. The reaction mixture was diluted with ethyl acetate and separated. The organic layer was washed with 10% hydrochloric acid and separated. The aqueous layer was neutralized with 10% sodium carbonate and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated under reduced pressure to give the product. EI-MS m / z 229, 231 (M + H) ⁺ .

Step C: Phenylmethyl (3 E) -4 - [(1 Z) -2-amino-1-aza-3- (4-bromophenyl) prop-1-enyloxy] but-3-enoate

To a stirred solution of 2- (4-bromophenyl) -1- (hydroxylmino) ethylamine (1.0 eq.) In ethanol (0.1 M) was added phenylmethylprop-2-ynate (2.0 eq.) At 25 ° C was added and stirred for 36 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (40% EtOAc / hexane). EI-MS m / z 389, 391 (M + H) ⁺ .

Step D: Phenylmethyl 2 - [(2-bromophenyl) methyl] imidazole-4-carboxylate

Phenylmethyl (3E) -4 - [(1Z) -2-amino-1-aza-3- (4-bromophenyl) prop-1-enyloxy] but-3-enoate in diphenyl ether at 200 ° C for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The reaction mixture was extracted with 10% hydrochloric acid. The aqueous layer was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was extracted with brine, and the organic layer was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / hexane). EI-MS m / z 369/371 (M + H) ⁺ .

Step E: Methyl (2E) -4- {2 - [(2-Bromophenyl) methyl] -4- [benzyloxycarbonyl] imidazolyl} but-2-enoate

To a stirred solution of phenylmethyl 2 - [(2-bromophenyl) methyl] imidazole-4-carboxylate in dimethylformamide (0.1 M) was added sodium hydride (1.2 eq.). The reaction mixture was allowed to stir for 10 minutes, followed by the addition of methyl 4-bromocrotonate, and stirring was continued for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was extracted with 10% hydrochloric acid and the aqueous layer was neutralized with saturated sodium carbonate. The aqueous layer was extracted with ethyl acetate and dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (50% EtOAc / hexane). EI-MS m / z 406/408 (M + H) ⁺ .

Step F: Methyl 2- {2- [benzyloxycarbonyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetate

To a solution of methyl (2E) -4- {2 - [(2-bromophenyl) methyl] -4- [benzyloxycarbonyl] imidazolyl} but-2-enoate in benzene was added tributyltin hydride (2 eq.) And 2.2 '. -Azobisisobutyronitrile (20% by weight) was added under nitrogen. The reaction mixture was refluxed under nitrogen for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (50% EtOAc / hexane). EI-MS m / z 391 (M + H) ⁺ .

Step G: 5 - [(Methoxycarbonyl) methyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepine-2-carboxylic acid

Methyl 2- {2- [benzyloxycarbonyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetate was dissolved in ethanol, followed by the addition of 10% palladium on carbon (10%, based on the weight) and subjected to hydrogenation at balloon pressure. After 3 hours the mixture was filtered through celite and submerged concentrated concentrated pressure to obtain a viscous oil.

Step H: Methyl 2- {2- [N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] -4H, 5H, 10H- benzo [d] imidazolo [1,2-a] azepin-5-yl} acetate

5 - [(methoxycarbonyl) methyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepine-2-carboxylic acid and 2- (1,2,3,4-tetrahydropyridino [2,3- b] pyridin-7-yl) ethylamine were dissolved in methylene chloride (0.1 M) with triethylamine (1.1 eq.) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.1 eq.) and Stirred for 18 hours at room temperature. The reaction mixture was diluted with methylene chloride and washed with water, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (10% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 459 (M + H) ⁺ .

Step I: 2- {2- [N- {2- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] -4H, 5H, 10H-benzo [ d] imidazolo [1,2-a] azepin-5-yl} acetic acid

To a stirred solution of methyl 2- {2- [N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] -4H, 5H, 10H-Benzo [d] imidazolo [1,2-a] azepine-5-yl} acetate in methanol (0.1M) was added to 1N NaOH (3 eq.). After 18 hours, the reaction mixture was neutralized with 10% HCl, concentrated by rotary evaporation, and purified by recrystallization from 2% MeOH / CH ₂ Cl ₂ . EI-MS m / z 431 (M + H) ⁺ .

Example 64

Preparation of 2- {2- [N- (methylethyl) -N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] -4H, 5H , 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetic acid

Step A: Methyl 2- {2- [N- (methylethyl) -N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] - 4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetate

5 - [(methoxycarbonyl) methyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepine-2-carboxylic acid and 2-N-methylethyl- (1,2,3,4-tetrahydropyridino [ 2,3-b] pyridin-7-yl) ethylamine were dissolved in methylene chloride (0.1 M) with triethylamine (1.1 eq.) And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.1 eq .) and stirred for 18 hours at room temperature. The reaction mixture was diluted with methylene chloride and washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (10% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 501 (M + H) ⁺ .

Step B: 2- {2- [N- (Methylethyl) -N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetic acid

To a stirred solution of methyl 2- {2- [N- (methylethyl) -N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl ] -4H, 5H, 10H Benzo [d] imidazolo [1,2-a] azepine-5-yl) acetate in methanol (0.1M) was added to 1N NaOH (3 eq.). After 18 hours, the reaction mixture was neutralized with 10% HCl, concentrated by rotary evaporation, and purified by recrystallization from 2% MeOH / CH ₂ Cl ₂ . EI-MS m / z 487 (M + H) ⁺ ; ¹ H-NMR (400 MHz, d-CDCl ₃ ): δ 7.50 (s, 1H), 7.34-7.09 (m, 4H), 6.20 (d, J = 6.3 Hz, 1H), 5.50 (m, 1H), 4.37-4.00 (m, 2H), 3.46-3.17 (m, 3H), 2.88 (m, 1H), 2.69 (m, 4H), 2.25 (d, J = 13.0 Hz, 2H), 1.86 (m, 3H), 1.60 (m, 7H).

Example 65

Preparation of 2- {2- [N- (methylethyl) -N (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-6-ylmethyl) carbamoyl] -4H, 5H-10H-benzo [d ] imidazolo [1,2-a] azepin-5-yl) acetic acid

Step A: (Methylethyl) (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-ylmethyl) amine

To a solution of 1,2,3,4-tetrahydropyridino [2,3-b] pyridine-7-carbaldehyde in anhydrous dichloromethane (32 ml) was added 4 ° A sieves, sodium sulfate and isopropylamine. The mixture was cooled to 0 ° C, followed by the addition of acetic acid (300 μl). The resulting mixture was stirred under nitrogen at room temperature for 18 hours. The mixture was filtered through celite, diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, concentrated by evaporation under reduced pressure and purified by flash chromatography (10% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 206 (M + H) ⁺ .

Step B: Methyl 2- {2- [N- (methylethyl) -N- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-6-ylmethyl) carbamoyl] -4H, 5H, 10H -benzo [d] imidazolo [1,2-a] azepin-5-yl} acetate

[(Methoxycarbonyl) methyl] -4H, 5H, 10H-benzo [d] imidazole [3,2-f] azepine-2-carboxylic acid was dissolved in methylene chloride (1 ml) followed by the addition of diisopropylethylamine (1.2 eq .) and EDC (1.2 eq.). Methyl ethyl (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-ylmethyl) amine was dissolved in methylene chloride (1 ml) and added to the resulting mixture. The reaction mixture was stirred at room temperature for 18 hours, concentrated by rotary evaporation and purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 488 (M + H) ⁺ .

Step C: 2- {2- [N- (Methylethyl) -N- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-6-ylmethyl) carbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl) acetic acid

Methyl 2- {2- [N- (methylethyl) -N- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-6-ylmethyl) carbamoyl] -4H, 5H, 10H-benzo [ d] imidazolo [1,2-a] azepine-5-yl} acetate was dissolved in methanol (0.2 M) followed by the addition of 1 N NaOH (5 eq.). The mixture was stirred at room temperature for 18 hours, acidified with 1N NaOH, concentrated by rotary evaporation, and the product was purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 474 (M + H) ⁺ ; ¹ H-NMR (400 MHz, MeOH-d ₄ ): δ 7.43-7.10 (m, 6H), 6.5 (s, 1H), 5.45 (s, 2H), 4.53- 4.40 (m, 3H), 4.12-3.83 (m, 3H), 3.40 (m, 2H), 2.70 (m, 3H), 2.55 (m, 1H), 1 , 85 (m, 2H), 1.15 (d, J = 6.33 Hz, 6H).

Example 66

Preparation of 2- {2- [N- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-6-ylmethyl) carbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1, 2-a] azepin-5-yl} acetic acid

Step A: Dimethoxypyridino [3,2-e] pyridin-2-ylmethane

A mixture of 2-aminopyridine-3-carbaldehyde, prepared according to Duggan, ME, WO 98/18460 Methylglyoxal dimethyl acetal (4 eq.) And L-proline (0.3 eq.) In MeOH (0.2 M) was refluxed under nitrogen for 20 hours. The mixture was cooled to room temperature, concentrated by rotary evaporation and the residue was diluted with methylene chloride (32 ml) and washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (10% MeOH / CH ₂ Cl ₂ ). ¹ H-NMR (400 MHz, CDCl _3): 9.15 (dd, J = 1.95, J = 4.20, 1H), 8.25 (d, J = 8.42, 1H), 8, 20 (dd, J = 1.95, 8.14, 1H), 7.8 (d, J = 8.36, 1H), 7.52 (q, J = 4.24, 1H), 5.5 (s, 1H), 3.5 (s, 6H).

Step B: Dimethoxy-1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-ylmethane

Dimethoxypyridino [3,2-e] pyridin-2-ylmethane was dissolved in methanol (0.5 M) followed by the addition of 10% Pd / C and hydrogenation at balloon pressure. The mixture was filtered through celite and concentrated by rotary evaporation. EI-MS m / z 209 (M + H) ⁺ .

Step C: 1,2,3,4-Tetrahydropyridino [2,3-b] pyridine-7-carbaldehyde

Dimethoxy-1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-ylmethane was dissolved in trifluoroacetic acid (14 ml) and stirred under nitrogen for 16 hours. The mixture was quenched with saturated sodium bicarbonate, extracted with methylene chloride, dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 163 (M + H) ⁺ .

Step D: 1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-ylmethylamine

Hydroxylamine hydrochloride (2 eq.), Sodium acetate trihydrate (2 eq.) And water (0.4 M) were heated to 60 ° C. 1,2,3,4-Tetrahydropyridino [2,3-b] pyridine-7-carbaldehyde was dissolved in methanol (2.5 ml) and added to the resulting solution. Additional methanol was added until the solution became clear; the reaction mixture was heated to 60 ° C for 18 hours. The mixture was cooled to room temperature, diluted with water (25 ml) and extracted with ether. The organic layer was extracted with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. To a solution of the oxime in trifluoroacetic acid (5 ml) was added zinc dust (5.6 eq.) In a few portions, keeping the temperature between 15-25 ° C. After stirring for 15 minutes, the mixture was added to an aqueous solution of 2N NaOH (39 ml) and methylene chloride (21 ml) at 0 ° C, and the mixture was stirred for additional 15 minutes. The reaction mixture was filtered, and the organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the product. EI-MS m / z 163 (M + H) ⁺ .

Step E: Methyl 2- {2- [N- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-6-ylmethyl) carbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetate

5 - [(Methoxycarbonyl) methyl] -4H, 5H, 10H-benzo [d] imidazole [3,2-f] azepine-2-carboxylic acid was dissolved in methylene chloride (0.5 ml) followed by addition of diisopropylethylamine ( 1.2 eq.) And EDC (1.2 eq.). 1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-ylmethylamine was dissolved in methylene chloride (0.5 ml) and added to the resulting solution. The reaction mixture was stirred at room temperature for 48 hours, concentrated under reduced pressure and purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 446 (M + H) ⁺ .

Step F: 2- {2- [N- (1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-6-ylmethyl) carbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1 , 2-a] azepin-5-yl} acetic acid

Methyl-2-2- [N- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-6-ylmethyl) carbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2 -a] azepin-5-yl} acetate was dissolved in MeOH (6 ml) and 1N NaOH (5 eq.) was added. The mixture was stirred at room temperature for 18 hours, acidified with 1N HCl, concentrated under reduced pressure, and the product was purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 432 (M + H) ⁺ . ¹ H-NMR (400 MHz, MeOH-d _4): δ 7.55 (s, 1H), 7.38 to 7.10 (m, 6H), 6.5 (d, J = 5.77, 1H ), 4.54-4.46 (m, 2H), 4.37 (s, 2H), 4.10 (d, J = 15.6, 2H), 3.95 (t, J = 11.79 , 2H), 3.30 (m, 2H), 2.7 (m, 2H), 2.5 (m, 1H), 1.85 (m, 2H).

Example 67

Preparation of 2- (2- {N -methyl-N- [3- (2-pyridylamino) -propyl] carbamoyl} -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl )acetic acid

Step A: Methyl 2- (2- {N -methyl-N- [3- (2-pyridylamino) -propyl] carbamoyl} -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepine 5-yl) acetate

[(Methoxycarbonyl) methyl] -4H, 5H, 10H-benzo [d] imidazole [3,2-f] azepine-2-carboxylic acid was dissolved in methylene chloride (0.5 ml) followed by the addition of diisopropylethylamine (1, 2 eq.) And EDC (1.2 eq.). 1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-ylmethylamine was dissolved in methylene chloride (0.5 ml) and added to the resulting solution. The reaction mixture was stirred at room temperature for 48 hours, concentrated under reduced pressure and purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 448 (M + H) ⁺ .

Step B: 2- (2- {N-Methyl-N- [3- (2-pyridylamino) -propyl] -carbamoyl} -4 H, 5 H, 10 H -benzo [d] imidazolo [1,2-a] azepine-5 yl) acetic acid

Methyl-2- (2- {N-methyl-N- [3- (2-pyridylamino) propyl] carbamoyl} -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl ) acetate was dissolved in MeOH (6 mL) and 1 N NaOH (5 eq.) was added. The mixture was stirred at room temperature for 18 hours, acidified with 1N HCl, concentrated under reduced pressure, and the product was purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 434 (M + H) ⁺ . ¹ H-NMR (400 MHz, CDCl _3): δ 8.0 (d, J = 5.4, 1H), 7.4 (m, 2H), 7.3 (m, 4H), 6.55 ( m, 3H), 4.20-4.05 (m, 4H), 3.9 (m, 1H), 3.3 (t, J = 6.8, 2H), 3.15 (s, 3H) , 2.7 (dd, J = 16.5, J = 6.3, 2H), 1.9 (m, 2H).

Example 68

Preparation of 2- (2- {N -methyl-N- [2- (2-pyridylamino) ethyl] carbamoyl} -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl )acetic acid

Step A: Methyl 2- (2- {N -methyl-N- (2- (2-pyridylamino) ethyl] carbamoyl} -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepine 5-yl) acetate

[(Methoxycarbonyl) methyl] -4H, 5H, 10H-benzo [d] imidazole [3,2-f] azepine-2-carboxylic acid was dissolved in methylene chloride (0.5 ml) followed by the addition of diisopropylethylamine (1, 2 eq.) And EDC (1.2 eq.). 1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-ylmethylamine was dissolved in methylene chloride (0.5 ml) and added to the resulting solution. The reaction mixture was stirred at room temperature for 48 hours, concentrated under reduced pressure and purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 434 (M + H) ⁺ .

Step B: 2- (2- {N-Methyl-N- [2- (2-pyridylamino) ethyl] carbamoyl} -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepine-5 yl) acetic acid

Methyl-2- (2- {N-methyl-N- [2- (2-pyridylamino) ethyl] carbamoyl} -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl ) acetate was dissolved in MeOH (6 mL) and 1 N NaOH (5 eq.) was added. The mixture was stirred at room temperature for 18 hours, acidified with 1N HCl, concentrated under reduced pressure, and the product was purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 420 (M + H) ⁺ . ¹ H NMR (400 MHz, d ₆ -DMSO): δ 12.35 (s, 1H), 7.5 (s, 1H), 7.33-7.16 (m, 8H), 6.5 ( bs, 1H), 4.4 (m, 1H), 4.10-3.8 (m, 4H), 3.15 (s, 3H), 2.9 (m, 2H), 2.8-2 , 6 (m, 2H), 1.75 (s, 2H).

Example 69

Preparation of 2- {2- [N- (benzimidazol-2-ylmethyl) -N-methylcarbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetic acid

Step A: Methyl 2- {2- [N- (benzimidazol-2-ylmethyl) -N-methylcarbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetate

[(Methoxycarbonyl) methyl] -4H, 5H, 10H-benzo [d] imidazole [3,2-f] azepine-2-carboxylic acid was dissolved in methylene chloride (0.5 ml) followed by the addition of diisopropylethylamine (1, 2 eq.) And EDC (1.2 eq.). 1,2,3,4-Tetrahydropyridino [2,3-b] pyridin-7-ylmethylamine was dissolved in methylene chloride (0.5 ml) and added to the resulting solution. The reaction mixture was stirred at room temperature for 48 hours, concentrated under reduced pressure and purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 444 (M + H) ⁺ .

Step B: 2- {2- [N- (Benzimidazol-2-ylmethyl) -N-methylcarbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetic acid

Methyl 2- {2- [N- (benzimidazol-2-ylmethyl) -N-methylcarbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetate was prepared in MeOH (6 mL) was dissolved and 1 N NaOH (5 eq.) Was added. The mixture was stirred at room temperature for 18 hours, acidified with 1N HCl, concentrated under reduced pressure, and the product was purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 430 (M + H) ⁺ . ¹ H-NMR (400 MHz, MeOH-d _4): δ 7.42 (s, 1H), 7.17 (m, 8H), 4.4 (m, 2H), 4.10 to 3.90 ( m, 4H), 3.3 (m, 2H), 3.0 (m, 2H), 2.10 (m, 2H).

Example 70

Preparation of methyl 2- (8-methoxy-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H , 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Methyl 2- (8-methoxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate (1 eq, prepared according to Example 56) was treated under nitrogen with 20% phosgene (1, 1 eq.) In toluene for 10 minutes. The excess phosgene was removed by rotary evaporation and the crude product was dissolved in 1: 1 THF / DMF (0.25 M) followed by the addition of diisopropylethylamine (1.1 eq.) And 3- (1,2,3, 4-Tetrahydropyridino [2,3-b] pyridin-7-yl) propylamine (1.1 eq., Prepared according to Duggan, ME. WO 98/18460 ). The reaction mixture was stirred under nitrogen for 12 h at rt, concentrated under reduced pressure, and the product was purified by flash chromatography (2 to 5% MeOH / CH ₃ Cl) to give methyl 2- (8-methoxy-2-). (N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5 yl) acetate as a clear oil.
EI-MS m / z 467 (M + H) ⁺ .

Example 71

Preparation of 2- (8-methoxy-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3-blipyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H -benzo [e] azaperhydroepin-5-yl) acetic acid

A 1N NaOH solution (3 eq.) Was added to a solution of methyl 2- (8-methoxy-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate (1 eq.) in methanol (0.10 M) was added and the resulting mixture became Stirred for 12 hours under nitrogen. The mixture was neutralized to pH = 7 with a 1N HCl solution and concentrated under reduced pressure. Purification by flash chromatography on silica gel (4 to 6% MeOH / CH ₂ Cl ₂ ) gave 2- (8-methoxy-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3 -b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetic acid as a white solid. EI-MS m / z 453 (M + H) ⁺ ; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 11.0 (br s, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.84 (d, J = 2.5 Hz, 1H), 6.70 (dd, J = 8.4, 2.5 Hz, 1H), 6.27 (d, J = 7 , 3 Hz, 1H), 5.74 (m, 1H), 4.65 (d, J = 15.1 Hz, 1H), 4.41 (d, J = 15.1 Hz, 1H), 3, 72 (s, 3H), 3.66 (m, 1H), 3.45 (m, 4H), 3.30 (m, 1H), 3.16 (m, 1H), 2.69 (m, 6H), 2, 12 (m, 1H), 1.87 (m, 2H), 1.80 (m, 2H), 1.52 (m, 1H).

Example 72 (reference)

Preparation of 2- (8-Benzyloxy-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H , 5H-benzo [e] azaperhydroepin-5-yl acetic acid

Step A: Methyl 2- (8-hydroxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetic acid

Boron tribromide (2 eq.) Was added to a solution of methyl 2- (8-methoxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate (1 eq, prepared according to Example 56) ) in methylene chloride (0.1M) at -78 ° C and the resulting mixture was allowed to warm to RT under nitrogen with stirring. The reaction mixture was quenched with 10% HCl solution and washed with 1N HCl solution followed by brine. The combined aqueous layer was concentrated under reduced pressure to give 2- (8-hydroxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetic acid as a white solid. EI-MS m / z 222 (M + H) ⁺ .

Step B: Methyl 2- (8-hydroxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Thionyl chloride (1.2 eq.) Was added to a solution of 2- (8-hydroxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetic acid (1 eq.) In methanol (0 , 1 M) at 0 ° C and the resulting mixture was allowed to warm to RT with stirring under nitrogen. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride and washed with saturated NaHCO ₃ solution. The organics were dried over sodium sulfate and concentrated under reduced pressure to give methyl 2- (8-hydroxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate as a white solid. EI-MS m / z 236 (M + H) ⁺ .

Step C: Methyl 2- (2- (tert-butoxycarbonyl) -8-hydroxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Di-tert-butyl dicarbonate (1.1 eq.) Was added to a solution of methyl 2- (8-hydroxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate in methylene chloride ( 0.50M) at RT and the resulting mixture was stirred under nitrogen for 5 hours. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (10 to 20% EtOAc / hexane) to give methyl 2- (2- (tert-butoxycarbonyl) -8-hydroxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate as a clear oil. EI-MS m / z 336 (M + H) ⁺ .

Step D: Methyl 2- (2- (tert-butoxycarbonyl) -8-benzyloxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

NaH (1.2 eq.) Was added to a solution of methyl 2- (2- (tert-butoxycarbonyl) -8-hydroxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl). acetate (1 eq.) in THF (0.10 M) at 0 ° C under nitrogen. After 10 minutes benzyl bromide (1.2 eq.) Was added and the resulting mixture was allowed to warm to RT with stirring. The reaction was quenched with saturated NaHCO ₃ solution and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organics were dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by flash chromatography on silica gel (10 to 20% EtOAc / hexanes) to give methyl 2- (2- (tert-butoxycarbonyl) -8-benzyloxy 1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate as a clear oil. EI-MS m / z 426 (M + H) ⁺ .

Step E: Methyl 2- (8-benzyloxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Methyl 2- (2- (tert-butoxycarbonyl) -8-benzyloxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate (1 eq.) And 4.0 M HCl / Dioxane (5 eq.) Was stirred under nitrogen for 3 hours at RT. The solvents were removed by rotary evaporation and the residue was dissolved in methylene chloride and washed with 1N NaOH. The organics were dried over sodium sulfate and concentrated under reduced pressure to give methyl 2- (8-benzyloxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate as a white solid. EI-MS m / z 326 (M + H) ⁺ .

Step F: 2- (8-Benzyloxy-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Methyl 2- (8-benzyloxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate (1 eq.) Was added under nitrogen with 20% phosgene (1.1 eq Toluene stirred for 10 minutes. The excess phosgene was removed by rotary evaporation and the crude product was dissolved in 1: 1 THF / DMF (0.25 M) followed by the addition of diisopropylethylamine (1.1 eq.) And 3- (1,2,3,4 -Tetrahydropyridino [2,3, b] pyridin-7-yl) propylamine (1.1 eq, prepared according to Duggan, ME, WO 98/18460 ). The reaction mixture was stirred under nitrogen for 12 h at RT, concentrated under reduced pressure, and the product was purified by flash chromatography (2 to 5% MeOH / CH ₃ Cl) to give methyl 2- (8-benzyloxy-2-). (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5 yl) acetate as a clear oil. EI-MS m / z 543 (M + H) ⁺ .

Step G: Preparation of 2- (8-Benzyloxy-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetic acid

A 1N NaOH solution (3 eq.) Was added to a solution of methyl 2- (8-benzyloxy-2- (N- (3- (1,2,3,4-tetrahydropyridino) [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate (1 eq.) in methanol (0.10M) and the resulting mixture became Stirred for 12 hours under nitrogen. The mixture was neutralized to pH = 7 with 1N HCl solution and concentrated under reduced pressure. Purification by flash chromatography on silica gel (4 to 6% MeOH / CH ₂ Cl ₂ ) gave 2- (8-benzyloxy-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3 , b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetic acid as a white solid. EI-MS m / z 529 (M + H) ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 10.7 (br s, 1H), 7.39 (m, 6H), 7.04 (d, J = 8.4 Hz, 1H), 6, 91 (m, 1H), 6.83 (m, 1H), 6.31 (d, J = 7.2 Hz, 1H), 5.30 (s, 2H), 5.03 (br s, 2H) , 4.32 (m, 1H), 4.21 (m, 1H), 3.67 (m, 1H), 3.47 (m, 4H), 3.22 (m, 1H), 3.11 ( m, 1H), 2.70 (m, 6H), 1.90 (m, 3H), 1.74 (m, 2H), 1.63 (m, 1H).

Example 73 (reference)

Preparation of 2- (8-phenol-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H , 5H-benzo [e] azaperhydroepin-5-yl) acetic acid

Step A: Methyl 2- (2- (tert-butoxycarbonyl) -8-trifluoromethanesulfonyl-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Trifluoromethanesulfonic anhydride (1.1 eq.) Was added to a solution of methyl 2- (2- (tert-butoxycarbonyl) -8-hydroxy-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl). acetate (1 eq.), prepared according to Example 72, step C) and 2,6-lutidine (1.3 eq.) in methylene chloride (0.1 M) at 0 ° C, and the resulting Ml The mixture was stirred under nitrogen for 1 hour. Water was added, the organic layer was collected, washed with 1N HCl solution and dried over magnesium sulfate. Concentration under reduced pressure gave methyl 2- (2- (tert-butoxycarbonyl) -8-trifluoromethanesulfonyl-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate as a clear oil. EI-MS m / z 468 (M + H) ⁺ .

Step B: Methyl 2- (2 - ((tert-butyl) oxycarbonyl) -8-phenyl-1H.3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Toluene (0.1 M) was added to a degassed mixture of methyl 2- (2 - ((tert-butyl) oxycarbonyl) -8-trifluoromethanesulfonyl-1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl ) acetate (1 eq.), phenylboronic acid (2 eq.), tetrakis (triphenylphosphine) palladium (0) (0.1 eq.) and potassium carbonate (2 eq.) were added and the resulting mixture was heated to 90 ° C for 12 hours heated, concentrated under reduced pressure and purified by flash chromatography on silica gel (20% EtOAc / hexane) to give methyl 2- (2 - ((tert-butyl) oxycarbonyl) -8-phenyl-1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate as a clear oil. EI-MS m / z 396 (M + H) ⁺ .

Step C: Methyl 2- (8-phenyl-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Methyl 2- (2- (tert-butoxycarbonyl) -8-phenyl-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate (1 eq.) And 4.0 M HCl / Dioxane (5 eq.) Was stirred under nitrogen for 3 hours at RT. The solvents were removed by rotary evaporation and the residue was dissolved in methylene chloride and washed with 1N NaOH. The organics were dried over sodium sulfate and concentrated under reduced pressure to give methyl 2- (8-phenyl-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate as a clear oil. EI-MS m / z 296 (M + H) ⁺ .

Step D: 2- (8-Phenyl-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate

Methyl 2- (8-phenyl-1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate (1 eq.) Was added under nitrogen with 20% phosgene (1.1 eq.) In Toluene stirred for 10 minutes. The excess phosgene was removed by rotary evaporation and the crude product was dissolved in 1: 1 THF / DMF (0.25 M) followed by the addition of diisopropylethylamine (1.1 eq.) And 3- (1,2,3, 4-Tetrahydropyridino [2,3, b] pyridin-7-yl) propylamine (1.1 eq, prepared according to Duggan, ME, WO 98/18460 ). The reaction mixture was stirred under nitrogen for 12 h at RT, concentrated under reduced pressure, and the product was purified by flash chromatography (2 to 5% MeOH / CH ₃ Cl) to give methyl 2- (8-phenyl-2-). (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5 yl) acetate as a clear oil. EI-MS m / z 513 (M + H) ⁺ .

Step E: Preparation of 2- (8-phenyl-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetic acid

A 1N NaOH solution (3 eq.) Was added to a solution of methyl 2- (8-phenyl-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate (1 eq.) in methanol (0.10M) and the resulting mixture became Stirred for 12 hours under nitrogen. The mixture was neutralized to pH = 7 with 1N HCl solution and concentrated under reduced pressure. Purification by flash chromatography on silica gel (4 to 6% MeOH / CH ₂ Cl ₂ ) gave 2- (8-phenyl-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3 , b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetic acid as a white solid. EI-MS m / z 499 (M + H) ⁺ ; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 10.9 (br s, 1H), 7.41 (m, 6H), 7.09 (d, J = 8.4 Hz, 1H), 6, 93 (m, 1H), 6.85 (m, 1H), 6.29 (d, J = 7.2Hz, 1H), 5.57 (br s, 1H), 4.91 (br s, 1H ), 4.32 (m, 2H), 3.50 (m, 4H), 3.27 (m, 1H), 3.11 (m, 1H), 2.68 (m, 6H), 2.34 (m, 1H), 1.90 (m, 4H), 1.74 (m, 1H), 1.42 (m, 1H).

Example 74

Preparation of 2- (2- {N- [3- (2-amino-5H-1,3-thiazol-4-yl) -propyl] -carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepine-5 yl) acetic acid

Step A: Preparation of methyl 6-bromo-5-oxohexanoate

Ethyl 4-acetyl butyrate was dissolved in MeOH (0.5 M) and cooled to 0 ° C. Bromine (1.0 eq.) Was added dropwise and the mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in ether, washed with water, saturated sodium bicarbonate and brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (7% EtOAc / hexanes). EI-MS m / z 224 (M + H) ⁺ .

Step B: Preparation of methyl 4- (2-amino-3H-1,3-thiazol-4-yl) butanoate

Methyl 6-bromo-5-oxohexanoate and thiourea (1.2 eq.) In ethanol (0.2 M solution) were refluxed for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by flash chromatography (100% ethyl acetate). EI-MS m / z 201 (M + H) ⁺ .

Step C: Preparation of 4 - ((2-tert-butoxy) carbonylamino) -1,3-thiazol-4-yl) butanoic acid

Methyl 4- (2-amino-3H-1,3-thiazol-4-yl) butanoate was dissolved in methylene chloride followed by the addition of di-tert-butyl dicarbonate (1.1 eq.) And a catalytic amount of 4 - (dimethylamino) pyridine (DMAP). The resulting mixture was heated to reflux until the starting material was consumed, concentrated under reduced pressure, and the residue was purified by flash chromatography (60% hexanes / EtOAc). EI-MS m / z 401 (M + H) ⁺ . The ester was dissolved in ethanol and 1N NaOH was added. The reaction mixture was stirred for 18 hours, followed by the addition of 1N HCl. The mixture was concentrated under reduced pressure. EI-MS m / z 286 (MH) ^- .

Step D: Methyl 2- (2- (N- (3- (2-pyridylamino) prop-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate

Methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate hydrochloride was dissolved in methylene chloride and washed with 1N NaOH. The organic layer was separated, dried over sodium sulfate and concentrated by rotary evaporation. A solution of 4 - ((2-tert-butoxy) carbonylamino) -1,3-thiazol-4-yl) butanoic acid, triethylamine (2 eq.) In toluene (0.2 M solution) and DPPA (1.5 eq was refluxed for 2 hours, then methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate was added. The reaction mixture was heated at reflux overnight, brought to room temperature, concentrated and extracted with dichloromethane and water (1: 1). The organic layers were combined, dried over magnesium sulfate and concentrated under high vacuum. The resulting residue was purified by flash chromatography (10% MeOH / CH ₂ Cl ₂ ). EI-MS m / z 503 (M + H) ⁺ .

Step E: 2- (2- {N- [3- (2-Amino-5H-1,3-thiazol-4-yl) -propyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepine 5-yl) acetic acid

2- (2- {N- [3- (2-Amino-5H-1,3-thiazol-4-yl) propyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl ) Acetic acid was prepared by saponification of methyl 2- (2- (N- (3- (2-pyridylamino) prop-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl ) acetate in ethanol (60 ml) and 1N NaOH (20 ml). The mixture was stirred overnight at room temperature, acidified with 1N HCl, concentrated, and the residue was purified with dichloromethane than (CH ₂ Cl ₂ ) extracted. The organic solvent was concentrated and the residue was dissolved in 4.0 M HCl / dioxane and stirred at room temperature overnight. The mixture was concentrated under high vacuum and the residue was redissolved in acetonitrile to give the desired product. EI-MS m / z 389 (M + H) ⁺ .

Example 75

Preparation of 2- (2- (N- (4- (4,5-Dihydroimidazo-2-yl) -aminobut-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl )acetic acid

Step A: Methyl 2- (2- (N- (4-tert-butoxycarbonylaminobut-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate

Methyl 2- (1H, 2H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetate hydrochloride was dissolved in methylene chloride and washed with 1N sodium hydroxide. The organic layer was separated, dried over sodium sulfate and concentrated by rotary evaporation. The residue was stirred under nitrogen with 20% phosgene in toluene (0.1 M) for 10 minutes. After stirring, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (0.1 M), followed by the addition of diisopropylethylamine (1.5 eq.) And 4-tert-butoxycarbamoyl-1-yl-amine (1 , 2 eq.). The reaction mixture was stirred under nitrogen for 1 hour at 60 ° C, cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated sodium bicarbonate and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The product was purified by flash chromatography (EtOAc / hexane 1: 1 to 1: 0). EI-MS m / z 434 (M + H) ⁺ .

Step B: Methyl 2- (2- (N- (4-Aminobut-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate

Methyl 2- (2- (N- (4-tert-butoxycarbonylaminobut-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate was dissolved in HCl in ethyl acetate (1.17 M, 20 ml) for 12 hours at room temperature. The solvent was removed under reduced pressure and the residue was triturated with ether. The product was diluted with methylene chloride and extracted with sodium hydroxide (0.5 M). The organic phase was concentrated under reduced pressure and subjected to azeotropic distillation with toluene to give the product as a white solid. EI-MS m / z 334 (M + H) ⁺ .

Step C: 2- (2- (N- (4- (4,5-Dihydroimidazo-2-yl) -aminobut-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapine-5 yl) acetic acid

A solution of methyl 2- (2- (N- (4-aminobut-1-yl) carbamoyl) -1H, 3H, 4H-5H-benzo [e] azapin-5-yl) acetate, 4,5-dihydroimidazo 2-ylmethyl sulfide hydroiodide (2 eq.) And sodium bicarbonate (200 mg) in dioxane / water (3 mL / 2 mL) was heated at 100 ° C for 24 hours. The mixture was cooled to room temperature and the product was purified by preparative HPLC (18 mg). EI-MS m / z 388 (M + H) ⁺ ; ¹ H-NMR (400 MHz, MeOH-d4): δ 7.34 (d, J = 7.0 Hz, 1H), 7.28-7.20 (m, 3H), 4.60 (q, J = 15.0 Hz, 2H), 3.7-3.55 (m, 6H), 3.36 (m, 1H), 3.22-3.17 (m, 4H), 3.02 (t, J = Hz, 1H), 2.89-2.74 (m, 2H), 2.10-2.04 (m, 1H), 1.68-1.66 (m, 1H). 1.55-1.52 (m, 4H).

Example 76 (reference)

Preparation of 2- (2- (N- (4- (2-Propylcarbamoyl) aminobut-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

Step A: Methyl 2- (2- (N- (4-Aminobut-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate

Methyl 2- (2- (N- (4-aminobut-1-yl) carbamoyl) -1H, 3H, 4H-5H-benzo [e] azapin-5-yl) acetate was according to the procedure of Example 75.

Step B: 2- (2- (N- (4- (2-Propylcarbamoyl) aminobut-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid

A solution of methyl 2- (2- (N- (4-aminobut-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetate and 2-propyl isocyanate (1 Eq.) In ethyl acetate (2 ml) was heated at 60 ° C for 48 hours. The solvent was removed under reduced pressure and the residue was dissolved in methanol (0.1 M) and 1 N sodium hydroxide (3 eq.). The mixture was heated to 60 ° C for 24 hours. The product was purified by preparative HPLC as a white solid (TFA salt, 55.5 mg, 59%): EI-MS m / z 405 (M + H); ¹ H-NMR 400 MHz, MeOH-d4): 7.29-7.14 (m, 4H), 4.54 (q, J = 15.0 Hz, 2H), 3.79 (m, 1H), 3.66 (m, 1H), 3.54 (M, 2H), 3.15-3.06 (m, 4H), 2.84-2.79 (m, 1H), 2.74-2, 68 (m, 1H), 2.05-2.00 (m, 1H), 1.62-1.58 (m, 1H), 1.40-1.38 (m, 4H), 1.1 ( d, J = 6.8 Hz, 6H).

Example 77 (reference)

Preparation of methyl 2- {8-amino-2 - [(tert-butyl) oxycarbonyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate

Step A: (2-Bromo-5-nitrophenyl) methan-1-ol

To a stirred solution of 2-bromo-5-nitrobenzoic acid (1 eq.) In tetrahydrofuran (0.4 M) under nitrogen at 0 ° C was added BH ₃ / THF (1 M) (1.5 eq.). The reaction mixture was stirred at 70 ° C for 1 hour and quenched with methanol. The reaction mixture was concentrated under reduced pressure to obtain the product. EI-MS m / z 232 (M + H) ⁺ .

Step B: 2-Bromo-5-nitrobenzaldehyde

To a stirred solution of (2-bromo-5-nitrophenyl) methan-1-ol (1 eq.) In methylene chloride (0.1 M) at room temperature was added pyridinium chlorochromate (2 eq.). After 2 hours, the reaction mixture was filtered through celite and the product was purified by flash chromatography (15% EtOAc / hexane). EI-MS m / z 230 (M + H) ⁺ .

Step C: 3 - {[(2-Bromo-5-nitrophenyl) methyl] amino} propan-1-ol

To a stirred solution of 2-bromo-5-nitrobenzaldehyde (1 eq.) In methylene chloride (0.1 M) at Room temperature was added to 3-amino-1-propanol (2 eq.). After stirring for 4 hours, sodium triacetoxyborohydride (2 eq.) And acetic acid (5 eq.) Were added. The reaction mixture was stirred for 3 hours and carefully quenched with methanol. The organic phase was washed with saturated sodium bicarbonate and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash chromatography (10% EtOAc / hexane). EI-MS m / z 289 (M + H) ⁺ .

Step D: (tert -Butoxy) -N - [(2-bromo-5-nitrophenyl) methyl] -N- (3-hydroxypropyl) carboxamide

To a stirred solution of 3 - {[(2-bromo-5-nitrophenyl) methyl] amino} propan-1-ol (1 eq.) In tetrahydrofuran (0.07 M) and saturated sodium bicarbonate (20 eq.) At room temperature Di-tert-butyl dicarbonate (2 eq.) was added. After stirring for 4 hours, the solvent was removed by rotary evaporation and the residue was extracted with ethyl acetate. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (10% EtOAc / hexane). EI-MS m / z 389 (M + H) ⁺ .

Step E: (tert -Butoxy) -N - [(2-bromo-5-nitrophenyl) methyl] -N- (3-oxopropyl) carboxamide

To a stirred solution of (tert-butoxy) -N - [(2-bromo-5-nitrophenyl) methyl] -N- (3-hydroxypropyl) carboxamide (1 eq.) In methylene chloride (0.1 M) at room temperature Dess Martin reagent (1.2 eq.) Added. After stirring for 1.5 hours, the reaction mixture was quenched with ether, saturated sodium bicarbonate, followed by the addition of solid sodium thiosulfate. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the product. EI-MS m / z 387 (M + H) ⁺ .

Step F: Methyl (2E) -5 - {(tert-butoxy) -N - [(2-bromo-5-nitrophenyl) methyl] carbonylamino} pent-2-enoate

To a stirred solution of (tert-butoxy) -N - [(2-bromo-5-nitrophenyl) methyl] -N- (3-oxopropyl) carboxamide (1 eq.) In 200 mL of tetrahydrofuran (0.06 M) Room temperature was added to methyl (triphenylphosphoranylidene) acetate (1.5 eq.). The reaction mixture was stirred at 80 ° C for 2 hours and the reaction solvent was removed by rotary evaporation. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / hexane). EI-MS m / z: 443 (M + H) ⁺ .

Step G: Methyl (2E) -5- {N - [(3-amino-6-bromophenyl) methyl] (tert -butoxy) carbonylamino} pent-2-enoate

To a stirred solution of methyl (2E) -5 - {(tert-butoxy) -N - [(2-bromo-5-nitrophenyl) methyl] carbonylamino} pent-2-enoate (1 eq.) In 20 mL of N , N-Dimethylformamide (0.1 M) at room temperature was added stannous chloride dihydrate (10 eq.). After stirring for 3 hours, the solvent was removed by rotary evaporation. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The mixture was filtered through celite. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / hexane).
EI-MS m / z 413 (M + H) ⁺ .

Step H: Methyl 2- {8-amino-2 - [(tert -butyl) oxycarbonyl] -1H, 3H, 4H-benzo [e] azepin-5-ylidene} acetate

To a stirred solution of methyl (2E) -5- {N - [(3-amino-6-bromophenyl) methyl] (tert-butoxy) carbonylamino} pent-2-enoate (1 eq.) In toluene (0, 08 M) at room temperature were added tetrakis (triphenylphosphine) palladium (0.03 eq.) And triethylamine (3 eq.). The reaction mixture was stirred at 100 ° C for 18 hours and filtered through celite. The reaction solvent was removed by rotary evaporation. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (30% EtOAc / hexane). EI-MS m / z 333 (M + H) ⁺ .

Step I: Methyl 2- {8-amino-2 - [(tert -butyl) oxycarbonyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate

To a stirred solution of methyl 2- {8-amino-2 - [(tert-butyl) oxycarbonyl] -1H, 3H, 4H-benzo [e] azepin-5-ylidene) acetate in 25 ml of ethanol at room temperature became 10 % Pd / C (0.01 M). The reaction mixture was stirred under hydrogenation conditions at balloon pressure. After stirring for 4 hours, the reaction mixture was filtered through Celite. The reaction solvent was removed by rotary evaporation. The residue was purified by flash chromatography (50% EtOAc / hexane). EI-MS m / z 335 (M + H) ⁺ .

Example 78

Preparation of 2- {8-chloro-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) -propyl) carbamoyl] -1H, 3H, 4H , 5H-benzo [e] azepin-5-yl} acetic acid

Step A: Methyl 2- {2 - [(tert -butyl) oxycarbonyl] -8-chloro-1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate

To a stirred solution of copper (II) chloride (1.2 eq.) In anhydrous acetonitrile (0.3 M) was added tert-butyl nitrite (1.5 eq.) By syringe at room temperature under nitrogen. The resulting dark green suspension was then heated to 65 ° C for 15 minutes. Methyl 2- {8-amino-2 - [(tert -butyl) oxycarbonyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate (1 eq.) In acetonitrile (0.13 M) was added slowly over 5 minutes. The resulting black solution was heated to 65 ° C for 1 hour. The reaction mixture was diluted with methylene chloride and aqueous ammonium hydroxide. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (30% EtOAc / hexane). EI-MS m / z 353 (M + H) ⁺ .

Step B: Methyl 2- {8-chloro-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate

A solution of methyl 2- {2 - [(tert-butyl) oxycarbonyl] -8-chloro-1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate (1 eq.) In Figure 1, 17 M HCl / ethyl acetate (30 eq.) Was stirred at room temperature for 18 h. The reaction mixture was concentrated and dried in a vacuum oven. The resulting residue was dissolved in methylene chloride (0.15 M) followed by the addition of phosgene / toluene (20%) (10 eq.) Under nitrogen. After stirring for 1 hour, the solvent was removed by rotary evaporation. The residue was dissolved in 1 ml of N, N-dimethylformamide (0.07 M), followed by the addition of 3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propylamine (2 eq.) And N, N-diisopropylethylamine (10 eq.). The reaction mixture was heated to 50 ° C for 2 hours. The reaction solvent was removed by rotary evaporation and the residue was purified by flash chromatography (5% methanol / methylene chloride). EI-MS m / z 471 (M + H) ⁺ .

Step C: 2- (8-Chloro-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid

To a stirred solution of methyl 2- {8-chloro-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] - 1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate (1 eq.) In tetrahydrofuran (0.05 M) and water (0.05 M) was added lithium hydroxide monohydrate (1.5 eq. ) was added. The reaction mixture was stirred at room temperature for 10 hours. 1 M hydrogen chloride (1.5 eq.) Was added and the reaction solvent was evaporated under reduced pressure. The residue was diluted with 5% MeOH / CH ₂ Cl ₂ and the precipitate was filtered off. The filtrate was concentrated and dried in a vacuum oven for 24 hours to give the product. EI-MS m / z 457 (M + H) ⁺ ; ¹ H-NMR (CD ₃ OD, 400 MHz): δ 7.53 (d, J = 7.3 Hz, 1H), 7.39 (s, 1H), 7.18 (s, 2H), 6, 51 (d, 7.3 Hz, 1H), 4.56 (s, 2H), 3.80-3.45 (m, 5H), 3.21 (m, 2H), 2.80 (m, 4H), 2.75 (m, 2H ), 2.00-1.50 (m, 6H).

Example 79

Preparation of 2- {8-bromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) -propyl) carbamoyl] -1H, 3, 4H , 5H-benzo [e] azepin-5-yl} acetic acid

Step A: Methyl 2- {2 - [(tert -butyl) oxycarbonyl] -8-bromo-1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate

To a stirred solution of copper (II) bromide (1.3 eq.) In anhydrous acetonitrile (0.22 M) was added tert-butylnitrite (1.8 eq.) Under nitrogen through a syringe at room temperature. The resulting dark green suspension was then heated to 65 ° C for 15 minutes. Methyl 2- {8-amino-2 - [(tert -butyl) oxycarbonyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate (1 eq.) In acetonitrile (0.1 M) was added slowly over 5 minutes. The resulting black solution was heated to 65 ° C for 2 hours. The reaction mixture was diluted with methylene chloride and aqueous ammonium hydroxide. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (30% EtOAc / hexane). EI-MS m / z 398 (M + H) ⁺ .

Step B: Methyl 2- {8-bromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate

Methyl 2- {8-bromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H , 5H-benzo [e] azepin-5-yl} acetate was prepared from methyl 2- {2 - [(tert-butyl) oxycarbonyl] -8-bromo-1H, 3H, 4H, 5H-benzo [e] azepine. 5-yl) acetate was prepared according to the method of Example 34. EI-MS m / z 515 (M + H) ⁺ .

Step C: 2- {8-Bromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid

2- {8-bromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H benzo [e] azepin-5-yl} acetic acid was prepared from methyl 2- {8-bromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridine). 7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate was prepared according to the method of Example 34. EI-MS m / z 501 (M + H) ⁺ ; ¹ H-NMR (CD ₃ OD, 400 MHz): δ 7.55 (m, 2H), 7.34 (d, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6, 51 (d, J = 7.3 Hz, 1H), 4.57 (s, 2H), 3.80-3.45 (m, 5H), 3.21 (m, 2H), 2.76 (m , 4H), 2.52 (m, 2H), 2.00-1.50 (m, 6H).

Example 80

Preparation of 2- {7,8-dibromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) -propyl) carbamoyl] -1H, 3H , 4H, 5H-benzo [e] azepin-5-yl} acetic acid

Step A: Methyl 2- {7,8-dibromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] - 1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate

During the column chromatography of methyl 2- {8-bromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H , 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate was methyl 2- {7,8-dibromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2 , 3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate. EI-MS m / z 594 (M + H) ⁺ .

Step B: 2- {7,8-Dibromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid

2- {7,8-dibromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H , 5H-benzo [e] azepin-5-yl} acetic acid was prepared from methyl 2- {7,8-dibromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3- b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate prepared according to the method of Example 34. EI-MS m / z 580 (M + H) ⁺ ; ¹ H-NMR (CD ₃ OD, 400 MHz). δ 7.67 (s, 1H), 7.53 (d, J = 7.4Hz), 7.49 (s, 1H), 6.50 (d, J = 7.4Hz, 1H), 4 , 88 (s, 2H), 3.45-3.80 (m, 5H), 3.21 (m, 2H), 2.76 (m, 4H), 2.50 (m, 2H), 2, 00-1.50 (m, 6H).

Example 81 (reference)

Preparation of 2- {8 - [(methylsulfonyl) amino] -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] - 1H, 3H,4H, 5H-benzo [e] azepin-5-yl} acetic acid

Step A: Methyl 2- [2 - [(tert -butyl) oxycarbonyl] -8 - [(methylsulfonyl) amino] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate

To a stirred solution of methyl 2- {8-amino-2 - [(tert-butyl) oxycarbonyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate (1 eq.) In Methylene chloride (0.1 M) was added at room temperature to methanesulfonyl chloride (1.1 eq.) And triethylamine (5 eq.). After stirring for 5 hours, the reaction mixture was diluted with methylene chloride. The organic phase was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / hexane). EI-MS m / z 413 (M + H) ⁺ .

Step B: Methyl 2- {8 - [(methylsulfonyl) aminol-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H,4H, 5H-benzo [e] azepin-5-yl} acetate

Methyl 2- {8 - [(methylsulfonyl) amino] -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] - 1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate was prepared from methyl 2- {2 - [(tert-butyl) oxycarbonyl] -8 - [(methylsulfonyl) amino] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate was prepared according to the method of Example 34. EI-MS m / z 530 (M + H) ⁺ .

Step C: 2- {8 - [(Methylsulfonyl) amino] -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H,4H,5H-benzo [e] azepin-5-yl) acetic acid

2- {8 - [(methylsulfonyl) amino] -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetic acid was prepared from methyl 2- {8 - [(methylsulfonyl) amino] -2- [N- (3- (1,2,3,4 tetrahydropyridino [2,3-b] pyridin-7-yl) -propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate was prepared according to the method of Example 34.
EI-MS m / z 516 (M + H) ⁺ ; ¹ H-NMR (CD ₃ OD); 400 MHz): δ 7.52 (d, J = 7.3 Hz, 1H), 7.28 (s, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.05 ( d, J = 6.6 Hz, 1H), 6.51 (d, J = 14.7 Hz, 1H), 4.55 (s, 2H), 3.70-3.50 (m, 5H), 3.21 (m, 2H), 2.92 (s, 3H), 2.75 (m, 4H), 2.55 (m, 2H), 2.00-1.60 (m, 6H).

Example 82 (reference)

Preparation of 2- {8 - [(phenylsulfonyl) amino] -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid

Step A: Methyl 2- {2 - [(tert -butyl) oxycarbonyl] -8 - [(phenylsulfonyl) amino] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate

To a stirred solution of methyl 2- {8-amino-2 - [(tert-butyl) oxycarbonyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate (1 eq.) In Methylene chloride (0.1 M) was added benzenesulfonyl chloride (1.1 eq.) And triethylamine (5 eq.) At room temperature. After stirring for 5 hours, the reaction mixture was diluted with methylene chloride. The organic phase was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / hexane). EI-MS m / z 475 (M + H) ⁺ .

Step B: Methyl 2- {8 - [(phenylsulfonyl) amino] -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl ) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate

Methyl 2- {8 - [(phenylsulfonyl) amino] -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] - 1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate was prepared from methyl 2- {2 - [(tert-butyl) oxycarbonyl] -8 - [(phenylsulfonyl) amino] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate was prepared according to the method of Example 34. EI-MS m / z 592 (M + H) ⁺ .

Step C: 2- {8 - [(Phenylsulfonyl) amino] -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid

2- {8 - [(phenylsulfonyl) amino] -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid was prepared from methyl 2- {8 - [(phenylsulfonyl) amino] -2- [N- (3- (1,2,3,4 tetrahydropyridino [2,3-b] pyridin-7-yl) -propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate was prepared according to the method of Example 34.
EI-MS m / z 578 (M + H) ⁺ ; ¹ H-NMR (CD ₃ OD, 400 MHz): δ 7.71 (d, J = 7.2 Hz, 2H), 7.51 (m, 2H), 7.44 (d, 2H), 7, 22 (s, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 6.4 Hz, 1H), 6.51 (d, J = 7.2 Hz, 1H), 4.51 (s, 2H), 3.50-3.65 (m, 5H), 3.21 (m, 2H), 2.80-2.60 (m, 4H), 2 , 52 (m, 2H), 2.00-1.50 (m, 6H).

Example 83 (reference)

Preparation of 2- {8-carbonylamino-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H , 5H-benzo [e] azepin-5-yl} acetic acid

Step A: Methyl 2- (2 - [(tert -butyl) oxycarbonyl] -8 - {[(4-nitrophenyl) methoxycarbonylamino} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate

To a stirred solution of methyl 2- {8-amino-2 - [(tert-butyl) oxycarbonyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate (1 eq.) In Methylene chloride (0.1 M) was added at room temperature to 4-nitrobenzyl chloroformate (1.1 eq.) And triethylamine (5 eq.). After stirring for 5 hours, the reaction mixture was diluted with methylene chloride. The organic phase was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / hexane). EI-MS m / z 514 (M + H) ⁺ .

Step B: Methyl 2- (8 - {[(4-nitrophenyl) -methoxylcarbonylamino} -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl ) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate

Methyl-2- (8 - {[(4-nitrophenyl) methoxy] carbonylamino} -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate was prepared from methyl 2- (2 - [(tert -butyl) oxycarbonyl] -8 - [[(4-nitrophenyl ) methoxy] carbonylamino} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate prepared according to the method of Example 34.
EI-MS m / z 631 (M + H) ⁺ .

Step C: Methyl 2- {8-carbonylamino-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate

To a stirred solution of methyl 2- (8 - {[(4-nitrophenyl) methoxy] carbonylamino} -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridine -7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetate in ethanol (0.05M) at room temperature, 10% Pd / C (0.10M ) was added. After stirring for 4 h under hydrogen at balloon pressure, the reaction mixture was filtered through Celite. The reaction solvent was removed by rotary evaporation. The residue was purified by flash chromatography (50% EtOAc / hexane).
EI-MS m / z 480 (M + H) ⁺ .

Step D: 2- {8-Carbonylamino-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid

2- [8-carbonylamino-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H benzo [e] azepin-5-yl} acetic acid was prepared from methyl 2- {8-carbonylamino-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridine). 7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate was prepared according to the method of Example 34. EI-MS m / z 466 (M + H) ⁺ ; ¹ H-NMR (CD ₃ OD, 400 MHz): δ 7.98 (s, 1H), 7.60-7.20 (m, 4H), 6.56 (d, J = 7.3 Hz, 1H ), 4.60 (s, 2H), 3.70-3.40 (m, 2H), 3.30 (m, 2H), 2.80-2.70 (m, 4H), 2.63 ( m, 2H), 2.00-1.50 (m, 6H).

Example 84 (reference)

Preparation of 2- {8- (dimethylamino) -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) -propyl) carbamoyl] -1H, 3H , 4H, 5H-benzo [e] azepin-5-yl} acetic acid

Step A: Methyl 2- {8- (dimethylamino) -2 - [(tert -butyl) oxycarbonyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate

To a stirred solution of methyl 2- {8-amino-2 - [(tert-butyl) oxycarbonyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate (1 eq.) In Benzene (0.02 M) at room temperature was added Pd / C (10%) (20% by weight) and HCHO (37%) (20 eq.). After stirring for 4 h under hydrogen at balloon pressure, the reaction mixture was filtered through Celite. The reaction solvent was removed by rotary evaporation. The residue was purified by flash chromatography (50% EtOAc / hexane). EI-MS m / z 363 (M + H) ⁺ .

Step B: Methyl 2- (8- (dimethylamino) -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] - 1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate

Methyl 2- {8- (dimethylamino) -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H , 4H, 5H-benzo [e] azepin-5-yl} acetate was prepared from methyl 2- {8- (dimethylamino) -2 - [(tert-butyl) oxycarbonyl] -1H, 3H, 4H, 5H-benzo. e] azepin-5-yl} acetate was prepared according to the method of Example 34. EI-MS m / z 480 (M + H) ⁺ .

Step C: 2- {8- (Dimethylamino) -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid

2- {8- (dimethylamino) -2- {N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H , 5H-benzo [e] azepin-5-yl) acetic acid was prepared from methyl 2- {8- (dimethylamino) -2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3- b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetate was prepared according to the method of Example 34. EI-MS m / z 466 (M + H) ⁺ ; ¹ H-NMR (CD ₃ OD); 400 MHz): δ 7.51 (d, J = 7.4 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 6.91 (s, 1H), 6.71 ( m, 1H), 6.46 (d, J = 7.4Hz, 1H), 4.51 (m, 2H), 3.70-3.40 (m, 5H), 3.21 (m, 2H ), 2.92 (s, 6H), 2.80-2.70 (m, 4H), 2.69 (m, 2H), 2.00-1.50 (m, 6H).

Example 85

Using the above general description and examples, the following compounds were prepared. description Mass spectrum (M + H) 2- (2- (N- (2- (1,2,3,4-tetrahydro pyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e ] azapin-5-yl) acetic acid 409 2- (3- (N- (2- (1,2,3,4-tetrahydro pyridino (2,3-b) pyridin-7-yl) propyl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid 459 3- (2- (N- (2- (1,2,3,4-tetrahydro pyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e ] azapin-5-yl) propanoic acid 423 3- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) propyl) carbamoyl-1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) propanoic acid 437 3- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) propyl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) propanoic acid 473 3- {3- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 2H, 4H, 5H-benzo [d ] azepinyl} propanoic acid 437 acetic acid - [({N- [5- (2-pyridylamino) pentyl] carbamoyl} methyl) 1H, 2H, 4H, 5H-benzo [d] azepinyl (3 -] 2 425 2- [3 - ({3 - [(amidinoamino) methyl] phenyl} methyl) 1H, 2H, 4H, 5H-benzo [d] azepinyl] acetic acid -401 2- [3 - ({(5- (2-pyridylamino) pentyl] amino} sulfonyl) 1H, 2H, 4H, 5H-benzo [d] azepinyl] acetic acid 447 2- [3- (2 - {[4- (2-pyridylamino) butyl] amino} acetyl) 1H, 2H, 4H, 5H-benzo [d] azepinyl] acetic acid 411 2- (2- {N- [3- (5-methyl-1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl] carbamoyl} -1H, 3H, 4H, 5H -benzo [e] azepin-5-yl) acetic acid 437 2- [2 - ({N- [2- (2-pyridylamino) ethyl] carbamoyl} methyl) 1H, 3H, 4H, 5H-benzo [e] azepin-5-yl] acetic acid 383 2- {3 - acetic acid 1H, 2H, 4H, 5H-benzo [d] azepinyl) - [methyl ([(2-pyridylamino) methyl] phenyl} phenyl 4- {2)] 478 2- (3- {N- (2- (2-pyridylamino) ethyl) carbamoyl} -1H, 2H, 4H, 5H-benzo [d] azepinyl) acetic acid 369 2- {3- (N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl) -1H, 2H, 4H, 5H-benzo [d] azepine -1-yl) acetic acid 409 2- (8-fluoro-2- (N- (2- (1,2,3,4-tetrahydro pyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H, 5H -benzo [e] azapin-5-yl) acetic acid 427 2- {8-fluoro-2- [N- (2-pyridino [3,2-e] pyridin-2-ylethyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl} acetic acid 423 2- {8-fluoro-2- [N- (3- (1,2,3,4-tetrahydropyridino [3,2-e] pyridin-2-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H -benzo [e] azaperhydroepin-5-yl} acetic acid 441 2- (2- (N- (5- (6-Amino-5-methyl-2-pyridyl) pent-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl )acetic acid 426 2- (8-hydroxy-2- (N- (4- (2-pyridylamino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid 413 2- (2- (N- (2- (2-pyridylamino) ethyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid 369 2- {3- [N- (3-pyridino [3,2-e] pyridin-2-yl-propyl) carbamoyl] -1H, 2H, 4H, 5H-benzo [d] azepinyl} acetic acid 419 2- {2- [N- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-ylmethyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5- yl} acetic acid 395 2- [2- (N- {4 - [(4-methyl-2-pyridyl) amino] butyl} carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl] acetic acid 411 2- {2- [N- (4 - {[5- (trifluoromethyl) -2-pyridyl] amino} butyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid 465 2- [2- (N- {4 - [(5-chloro-2-pyridyl) amino] butyl} carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl] acetic acid 432 2- {2- [N- (4 - {[benzylamino] carbonylamino} butyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid 558 2- [2- (N- {4 - [(phenylamino) carbonylamino] butyl} carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl] acetic acid 553

Example 86

Under Use of the above general description and the above Examples can be the compounds of Tables 1 to 4 (in which OBn is benzyloxy) getting produced.

Table 1

Table 2

Table 3

Table 4

Example 87

Using the above general description and examples, the following compounds of Table 5 can be prepared. The groups B [2] A, B [3] A, IBA (I), IBA (II), TBA (I) and TBA (III) represent the ring systems as defined above. Table 5 EB (Alk) _p · Q-Alk) _q · AG 5-chlorobenzoxazol-2-yl 3- (5- (carboxymethyl) -9-methoxy-8-aza-B [2] A-2-yl) cyclopentylaminocarbonylmethyl 3,4,5,6-tetrahydro-pyrimid-2-ylmethylcarbonyl 2- (1-hydroxy-5- (carboxymethyl) -9-aza-B [3] A-3-ylcarbonyl) pyrrolidin-1-yl Pyrid-2-yl 4- (5- (carboxymethyl) -7,9-diaza-B [2] A-2-ylsulphonylamino) pyrid-2-ylmethyl 7-azabenzimidazole-2-yl ((4- (5- carboxymethyl) -6-aza-b [3] A-3-ylcarbonyl) piperid-1-yl) ethyl 2- 1,2,3,4-tetrahydro-1,8-naphthyrid-7-yl 2- (4- (7,8-dichloro-5- (carboxymethyl) -6-aza-B [3] A-3-ylcarbonyl) piperid-1-yl) ethyl 5,6,7,8-tetrahydropyrido [2,3-b] azepin-8-yl 3- (6- (Carboxymethyl-9-aza-IBA (I) -2-ylamino) prop-1-ylamino 3,4-dihydro-pyrido [3,2-b] 1,4-thiazin-6-yl 3- (6- (carboxymethyl) -IBA (I) -2-yloxy) ethylamino amidino ((4- (5- carboxymethyl) -8-aza-B [3] A-3-ylcarbonyl) piperid-1-yl) ethyl 2- 5,6-dimethyl benzimidazole-2-ylamino 4- (2- (5- (2-hydroxy-1-carboxyethyl) -7-aza-B [3] A-3-ylcarbonyl) ethenyl) phenylmethyl 4-methylimidazol-2-ylamino 2- (N-methyl-N- (6- (carboxymethyl) -IBA (I) -2-ylmethyl) aminocarbonyl) ethyl Oxazol-2-ylamino 3,3-dimethyl-5- (5- (1-carboxypropyl) -6,8-diaza-B [3] A-3-yl) pent-1-yl 6-methylpyrid-2-ylamino 2- (6- (5-carboxy-3-hydroxypentyl) -IBA (I) -2-ylaminosulphonyl) phenylmethyl 4,7-Diazabenzimidazol-2-ylamino 2- (6- (carboxymethyl) -8-methyl-9-aza-IBA (I) -2-ylmethoxy) ethyl 1,2,3,4-tetrahydro-1,8-naphthyrid-7-ylamino 3-hydroxy-5- (5- (1-carboxypropyl) -7-aza-B [3] A-3-yl) pent-1-yl (4-amidinophenyl) sulfonylamino 2- (6- (carboxymethyl) -8-methoxy-7-aza-IBA (I) -2-ylmethoxy) ethyl 3-Amidinophenylthiol 2- (6- (3-carboxyprop-1-yl) -IBA (I) -2-ylaminosulphonyl) phenylmethyl 4-Amidinopiperazin-1-yl 2-hydroxy-3- (5- (2-carboxyethyl) -7-methylthio-6,8-diaza-B [3] A-3-ylcarbonyl) prop-1-ylcarbonyl 3,4-dihydro-pyrido [3,2-b] -1,4-oxazin-6-ylamino 3- (5- (2-carboxyethyl) -7-aza-B [3] A-3-ylthio) prop-1-yl 3,4-dihydro-pyrido [3,2-b] -1,4-thiazine-6-ylamino 2- (6- (carboxymethyl) -7-aza-IBA (I) -2-ylmethoxy) ethyl 1,2,3,4-tetrahydro-1,8-naphthyrid-4-ylamino (5- (carboxymethyl) -7-aza-B [2] A-2-ylamino) methylcarbonyl 2-Amino-benzoxazole-5-ylaminocarbonylamino 2- (3-methyl-6- (carboxymethyl) -IBA (I) -2-ylcarbonylamino) cyclohexyl 5-aminoimidazole-2-ylaminosulfonylamino 3- (5- (2-carboxyethyl) -7-aza-B [3] A-3-ylthio) prop-1-yl 5-aminooxazol-2-ylmethyl 2-hydroxy-3- (5- (2-carboxyethyl) -7-methylthio-6,8-diaza-B [3] A-3-ylcarbonyl) prop-1-ylcarbonyl 2-aminoindole-5-yl 3- (6- (carboxymethyl) -IBA (I) -2-yloxy) ethyloxy 4-methyl-2-aminopyrid-6-yl (5- (2-carboxyethyl) -B [3] A-3-ylmethylcarbonylamino) methyl 2-Amino-7-azabenzoxazol-5-ylcarbonylamino 2- (6- (carboxymethyl) -IBA (I) -2-ylmethyl) carbonylamino) ethyl (1-methyl-2-amino-4-azabenzimidazole-5-ylamino) methylcarbonylamino 4- (6- (carboxymethyl) -IBA (I) -2-ylcarbonylamino) thien-2-ylmethyl 2-amino-4,7-diazabenzimidazol-5-yl 2- (6- (carboxymethyl) -9-aza-IBA (I) -2-ylamino) ethyl 2- (4,7-Diazabenzoxazol-5-ylamino) ethylsulfonylamino 4- (6- (carboxymethyl) -IBA (I) -2-ylaminomethyl) pyrimid-2-yl 2-amino-5-methyl-4,7-diazabenzoxazol-6-yl 3- (3- (6- (carboxymethyl) -10-aza-IBA (I) -2-ylamino) prop-1-yloxy) prop-1-yl (7-amino-1,2,3,4-tetrahydro-1,8-naphthyrid-1-ylmethyl) carbonylamino 2- (5- (carboxymethyl) -8-hydroxy-B [3] A-3-yl) ethylcarbonylamino) ethyl 2- (1,2,3,4-tetrahydro-1,8-naphthyrid-6-yl) ethoxy 3- (5- (2-carboxyethyl) -9-CF ₃ -8-aza-B [2] A-2-ylsulfonyl) -propyl 3-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazin-1-yl 3- (5- (carboxymethyl) -8,9-dimethoxy-B [2] A-2-ylcarbonylaminomethylcarbonyl) but-1-yl

Example 88

Biological studies

The following assays can be used to characterize the biological activity properties of the compounds of the invention. Purified integrin α _v β ₃ can be prepared using the methods of Marcinkiewicz et al. (Protein Expression Purif 8: 68-74, 1996) and Pytela et al. (Meth. Enzymol. 144: 475-489, 1987). Purified integrin α _v β ₅ can be prepared using the methods of Smith et al. (J. Biol. Chem. 265: 11008-11013, 1990). Purified integrin α _v β ₆ can be prepared using the methods of Busk et al. (J. Biol. Chem. 267: 5790-5796, 1992).

Primary human Umbilical cord endothelial cells (HUVEC) can be used to show that the compounds of the invention promote cell proliferation and / or cell adhesion inhibit.

HUVEC Proliferation Assay

• 1. Coat three NUNC polystyrene plates with 96 wells (VWR, 62409-120, cover 62409-118) with vitronectin (internally purified), fibronectin (Collaborative Biomed 40008A) or Fibrinogen (Calbiochem 341578), 50 ng / well in 50 μl PBS, 1 Hour at RT.
• 2. Trypsiniere HUVEC: a. Sink with 5 ml PBS (no Ca, Mg) b. 2 ml trypsin, remove c: 10 ml of growth medium
• 3. sink Vitronectin plates 1 × in 200 μl PBS - / - and place 3000 cells per well in 100 μl of growth medium (EBM2 (Clonetics, CC-3156) + EGM2 Bullet Kit (CC-4176)).
• 4. Incubate at 37 ° C for 24 hours to allow binding.
• 5. Remove growth medium and place 100 μl growth medium + active ingredients (25 μM and including by five-steps in DMSO at -0.25% DMSO final concentration).
• 6. Incubate for 3 days with replacement of the media (+ active ingredients).
• 7. Remove non-adherent cells on Friday with Raindance 12-well plate washer.
• 8. Wash twice with 200 μl PBS (+ Mg and Ca).
• 9. Pour off excess fluid from.
• 10. Freeze for 30 minutes at -70 ° C.
• 11. Thaw plate and place 150 μl of CyQuant fluorescent dye to (Molecular Probes C-7026).
• 12. Read after 4 minutes at λ = 485 (excitation) and λ = 530 (emission).

HUVEC adhesion assay

• 1. Coat two NUNC polystyrene plates with 96 wells (VWR, 62409-120, cover 62409-118) with 50 μl vitronectin (internally purified) at 50 ng / well in PBS (-Mg and Ca) for 1 hour at 37 ° C.
• 2nd sink with PBS and block with 50 μl PBS / 1% BSA (Sigma A8918) for 1 hour at 37 ° C.
• 3. Prepare drug dilutions: a. 400-fold concentrate in 100% DMSO b. 0.25% DMSO [assay] _final c. 10 mM and below (15 μM _final and below) d. Dilute 1 μL of the 400X concentrate in 200 μL of Adhesion Medium 4. Use 50 μ / well
• 4. Trypsiniere HUVEC: a. Rinse with 5 ml PBS (no Ca, Mg) b. 2 ml trypsin, remove c. 10 ml of growth medium
• 5. Centrifuge for 10 minutes at 1200 rpm.
• 6. sink Blocking buffer from the assay plate and place 50 μl of the drug dilutions to.
• 7. Suspend cells again in adhesion medium, count and add 2e4 cells / well in 50 μl (4e5 / ml).
• 8. Incubate for 60 minutes at 37 ° C.
• 9. Remove non-adherent cells with Raindance 12-well plate scrubber.
• 10. Wash twice with 200 μl PBS (+ Mg and Ca).
• 11. Pour off excess liquid from.
• 12. Freeze for 30 minutes Night at -70 ° C.
• 13. Thaw plate and place 150 μl of CyQuant fluorescent dye to (Molecular Probes C-7026).
• 14. Read after 2 to 5 minutes at λ = 485 (excitation) and λ = 530 (emission) from.

Adhesion Medium: Medium 199 (containing 36 mM CaCl ₂ and 0.8 mM MgSO ₄ ), 0.5% BSA, 10 mM HEPES, 1 mM MgCl ₂ and 1 mM MnCl ₂ .

Integrin binding assay

Purification of vitronectin

Vitronectin was obtained from outgrown human plasma as described by Yatohgo et al. (Cell Struct. Funct. 13: 281-292, 1988), with modifications. Normal human blood collected in citrate tubes was centrifuged and allowed to clot overnight with the addition of CaCl ₂ . The coagulum was centrifuged, filtered at 0.45 μm and applied to a heparin-Sepharose column equilibrated with 10 mM NaPO ₄ , 5 mM EDTA, 0.13 M NaCl, pH 7.7. The column flow was collected as a pool, urea was added to a final concentration of 8 M and mixed overnight. The sample was then incubated with heparin-Sepharose, the 7.7 (buffer A) had been equilibrated overnight with 10 mM NaPO _4, 5 mM EDTA, 8 M urea, pH. The heparin Sepharose was separated from the liquid by centrifugation and washed once with buffer A, buffer A + 0.13 M NaCl and buffer A + 0.13 NaCl and 10 mM BME. The vitronectin was eluted from the column with buffer A + 0.5 M NaCl. The fractions containing vitronectin were buffer buffered in PBS and stored at -70 ° C.

Ruthenylation of vitronectin and fibrinogen

Purified human vitronectin or purified human fibrinogen (Calbiochem) was dialysed in 50 mM borate, 100 mM NaCl, pH 8.0. A stock solution of ruthenium (II) -trisbipyridin-N-hydroxysuccinimide ester (Origen TAG ^® ester, Bettingen Inc. Gaithersburg, MD) was freshly prepared by adding 50 ul DMSO to 150 ug of the Origen TAG-NHS-ester. 50 μl of the Origen TAG NHS ester was added to a 1/5 molar ratio of the matrix protein. After 1 hour incubation at 25 ° C, the reaction was quenched by the addition of 50 μl 2 M glycine. Unincorporated ruthenium and excess glycine were removed by dialysis in PBS, 0.05% NaN ₃ . Protein concentrations were determined using Micro-BCA (Pierce, Rockford, IL). Oxigen TAG incorporation was determined at 455 nm (e = 13700 M ^-1 cm ^-1 ). Vitronectin-Ru and fibrinogen-Ru were stored at -70 ° C until needed.

Purification of platelet fibrinogen receptor α _IIb β ₃

Twelve units of drained platelets were washed with PBS and centrifuged at low speed to remove RBCs. The washed platelets were lysed in 20mM Tris-HCl, pH 7.4, 140mM NaCl, 2mM CaCl ₂ , 1mM Pefabloc, 3% octylglucoside under gentle stirring for 2 hours at 4 ° C. The lysate was centered at 100,000 x g for 1 hour to pellet insoluble cell debris. The resulting supernatant was applied to a lens-lectin column (EY labs) and washed with lysis buffer containing 1% octylglucoside (binding buffer) until a stable UV baseline was achieved. Purified α _IIb β ₃ was eluted from the column with binding buffer containing 10% dextrose. Purified α _IIb β ₃ was stored at -70 ° C until needed.

Purification of α _v β ₃ and α _v β ₅

Frozen placentas were thawed overnight at 4 ° C, cut into 1 cm pieces, and 50 mM Tris-HCl, 100 mM NaCl, 1 mM PMSF pH 7.5 (buffer A). The placentas were then incubated overnight in Buffer A with the addition of 3% (w / v) octylglucoside. The extracted protein was separated from the whole tissue by centrifugation. The extract was then filtered (0.45 μm) and NaN ₃ was added to a final concentration of 0.02%. The sample was then applied to an anti-α _v β ₃ or anti-α _v β ₅ affinity column, washed with buffer A + 1% (w / v) octylglucoside and eluted with Gentle Elution ^Buffer® (Pierce). The fractions containing α _v β ₃ or α _v β ₅ were changed to buffer A plus 1% octylglucoside and stored at -70 ° C. Purified α _v β ₃ and α _v β ₅ were also purchased from Chemicon International Inc.

Incorporation of α _v β ₃ , α _v β ₅ or alpha _IIb β ₃ on paramagnetic beads

α _v β ₃ -, α _v β ₅ - or α _IIb β ₃ -paramagnetische beads were made of uncoated 4.5 μ Dynabeads ^® (Dynal ^®, Lake Success, NY). Uncoated Dynabeads ^® were washed three times in phosphate buffered saline, pH 7.4 (PBS) and resuspended in 50 mM Tris-HCl, 100 mM NaCl, 1 mM MgCl _2, 1 mM CaCl ₂ and 1 m MnCl _2, pH 7.5 ( Buffer A) suspended. The purified receptors α _v β _3, α _v β ₅ (Chemicon) or α _IIb β ₃ were rapidly diluted in buffer A and added to the uncoated Dynabeads ^® in a ratio of 50 ug protein to 10 ⁷ beads. The bead suspension was incubated with shaking overnight at 4 ° C. The beads were washed three times in buffer A, 0.1% bovine serum albumin (BSA) and again buffer A + 3% BSA. After 3 hours at 4 ° C, the beads were washed three times in buffer A, 1% BSA, 0.05% azide and stored at 70 ° C until needed.

Solid phase binding assay

All compounds were resolved and serially diluted in 100% DMSO prior to final dilution in assay buffer (50mM Tris-HCl, pH 7.5, 100mM NaCl, 1mM CaCl ₂ , 1mM MgCl ₂ , 1mM MnCl ₂ , 1 % BSA, 0.05% Tween-20) containing vitronectin Ru or fibrinogen Ru and suitable integrin coated paramagnetic beads. The assay mixture was incubated for 2 hours at 25 ° C with shaking and then ^® on an Origen Analyzer (Igen Inc. Gaithersburg, MD.) Read. Non-specific binding was determined using 1 μM vitronectin, 1 μM fibrinogen or 5 mM EDTA. The data were obtained using a four-parameter fits through the Leven Castle-Marquardt algorithm (XLfit ^® ID Business Solutions). Ki values were calculated using the equation of Cheng and Prusoff (Biochem. Pharmacology 22: 3099-3108, 1973).

The following compounds have activity in the HUVEC proliferation assay and / or the HUVEC adhesion assay with IC ₅₀ values of 30 μM or less:
2- (2- (N- (3- (2-pyridylamino) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2- (N- (4- (2-pyridylamino) butyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2- (N- (5- (2-pyridylamino) pent-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2- (N-methyl-N- (4- (2-pyridylamino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2- (N- (4- (2-pyridylamino) -trans-cyclohexyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2 - (((4- (2-pyridylamino) methyl) piperid-1-yl) carbonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2- (N- (3- (2-pyridylamino) methylphenyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2- (N- (4 - ((6-methyl-2-pyridyl) amino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2- (N- (4- (pyrimidin-2-ylamino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2- (N- (3- (6-amino-2-pyridyl) prop-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2- (N- (3- (6- (tert-butoxycarbonylamino) -2-pyridyl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) prop-1-yl) carbamoyl) -1H, 3H, 4H, 5H -benzo [e] azapin-5-yl) acetic acid;
2- (2 - (((4- (2-pyridylamino) but-1-yl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2 - (((3- (2-pyridylamino) prop-1-yl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2- (2 - ((2- (2-pyridylamino) ethyl) amino) acetyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2- (2 - ((3- (2-pyridylamino) prop-1-yl) amino) acetyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2- (2 - ((4- (2-pyridylamino) but-1-yl) amino) acetyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2 - ((N- (3- (2-pyridylamino) prop-1-yl) carbamoyl) methyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2- (4- (2-pyridylamino) but-1-oxycarbonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (8-methoxy-2- (N- (4- (2-pyridylamino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetic acid;
2- (8-fluoro-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H -benzo [e] azaperhydroepin-5-yl) acetic acid;
2- (2 - ({N- (4- (2-pyridylamino) prop-1-yl) carbamoyl} methyl) -3-oxo-1H, 4H, 5H-benzo (e) azepin-5-yl) acetic acid;
2- (3 - ({N- (4- (2-pyridylamino) but-1-yl) carbamoyl} methyl) -1H, 2H, 4H, 5H-benzo [d] azepin-1-yl) acetic acid;
2- (3 - {[N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] methyl} -1H, 2H, 4H, 5H- benzo [d] azepinyl) acetic acid;
2- (3- {N- (5- (2-pyridylamino) pent-1-yl) carbamoyl} -1H, 2H, 4H, 5H-benzo [d] azepinyl) acetic acid;
2- {3- (N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl) -1H, 2H, 4H, 5H-benzo [d ] azepin-1-yl} acetic acid;
2- {3- (7- (2-pyridylamino) heptanoyl) -1H, 2H, 4H, 5H-benzo [d] azepin-1-yl} acetic acid;
2- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e ] azapin-5-yl) propanoic acid;
2- {2- [N- (methylethyl) -N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] -1H, 3H, 4H , 5H-benzo [e] azepin-5-yl} acetic acid;
2- (2-aza-2-cyano-1 - ((1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) amino) vinyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2 - (((2- (1,2,3,4-tetrahydro pyridino (2,3-b) pyridin-7-yl) ethyl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [ e] azapin-5-yl) acetic acid;
3- (2- (N- (2- (1,2,3,4-tetrahydro pyridino (2,3-b) pyridin-7-yl) ethyl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) propanoic acid;
2- (2- (N- (3- (2-pyridylamino) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2 - ((5R) -2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) prop-1-yl) carbamoyl) -1H, 3H , 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2 - ((5R) -2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H, 5H -benzo [e] azapin-5-yl) acetic acid;
2 - ((5S) -2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H, 5H -benzo [e] azapin-5-yl) acetic acid;
2 - ((5S) -2- (4- (1,2,3,4-tetrahydro pyridino (2,3-b) pyridin-7-yl) butanoyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [ e] azapin-5-yl) acetic acid;
2- [2- (4- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) butanoyl) -1H, 3H, 4H, 5H-benzo [e] azepin-5- yl] acetic acid;
2- {2- (N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetic acid;
2- {2- [N- (methylethyl) -N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] -4H, 5H, 10H -benzo [d] imidazolo [1,2-a] azepin-5-yl) acetic acid;
2- {2- [N- (methylethyl) -N- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-6-ylmethyl) carbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetic acid;
2- {2- [N- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-6-ylmethyl) carbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2- a] azepin-5-yl} acetic acid;
2- (2- {N-methyl-N- [3- (2-pyridylamino) propyl] carbamoyl} -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl) acetic acid;
2- (8-methoxy-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H -benzo [e] azaperhydroepin-5-yl) acetic acid;
2- (8-phenyl-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H -benzo [e] azaperhydroepin-5-yl) acetic acid;
2- (2- (N- (4- (4,5-dihydroimidazo-2-yl) aminobut-1-yl) carbamoyl) -1H, 3H, 4H-5H-benzo [e] azapin-5-yl) acetic acid ;
2- {8-chloro-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H -benzo [e] azepin-5-yl} acetic acid;
2- {8-bromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H -benzo [e] azepin-5-yl} acetic acid;
2- {7,8-dibromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H , 5H-benzo [e] azepin-5-yl} acetic acid;
2- (2- (N- (3- (6- (methylamino) -2-pyridyl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
2- (2- (N- (2- (1,2,3,4-tetrahydro pyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e ] azapin-5-yl) acetic acid;
2- (3- (N- (2- (1,2,3,4-tetrahydro pyridino (2,3-b) pyridin-7-yl) propyl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid;
3- (2- (N- (2- (1,2,3,4-tetrahydro pyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e ] azapin-5-yl) propanoic acid;
3- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) propyl) carbamoyl-1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) propanoic acid;
3- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) propyl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl] propanoic acid;
2 - acetic acid [3 ({N- [5- (2-pyridylamino) pentyl] carbamoyl} methyl) -1H, 2H, 4H, 5H-benzo [d] azepinyl];
2- [3- (2 - {[4- (2-pyridylamino) butyl] amino} acetyl) -1H, 2H, 4H, 5H-benzo [d] azepinyl] acetic acid;
2- (2- {N- [3- (5-methyl-1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl] carbamoyl} -1H, 3H, 4H, 5H -benzo [e] azepin-5-yl) acetic acid;
2- (3- {N- (2- (2-pyridylamino) ethyl) carbamoyl} -1H, 2H, 4H, 5H-benzo [d] azepinyl) acetic acid;
2- {3- (N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl) -1H, 2H, 4H, 5H-benzo [d ] azepin-1-yl} acetic acid;
2- (8-fluoro-2- (N- (2- (1,2,3,4-tetrahydro pyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H, 5H -benzo [e] azapin-5-yl) acetic acid;
2- [2- (N- {4 - [(4-methyl-2-pyridyl) amino] butyl} carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl] acetic acid; and
2- {2- [N- (4 - {[benzylamino] carbonylamino} butyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid.

Compounds of the invention can be shown to inhibit vitronectin α _v β ₃ binding in vitronectin α _v β ₃ binding assays and osteoclasts-mediated bone resorption in bone resorption pitassays as described in Woo et al. (Eur. J. Pharm. 300: 131-135, 1996), EP 528587 . WO 97/01540 . WO 98/18461 and WO 99/30713 described, inhibit. Compounds of the invention can be shown to promote smooth muscle cell migration in human aortic smooth muscle cell migration assay described in U.S. Patent Nos. 4,646,695 and 4,357,237 WO 97/01540 and Liaw et al., J. Clin. Invest. 95: 713-724, 1995, inhibit.

Compounds of the invention can be shown to inhibit vitronectin α _v β ₅ and / or α _v β binding in vitronectin α _v β ₅ and α _v β ₆ binding assays, as described in U.S. Pat WO 99/30709 and WO 99/30713 described, inhibit. Compounds of the invention can be shown to have the α ₅ β ₁ integrin binding in α ₅ β ₁ integrin binding assays such as WO 99/98139 described, inhibit.

Compounds of the invention can be shown to have anti-bone resorption properties in a rat animal model, described in U.S. Pat WO 97/01540 and Wronski et al., Cells and Mat. 1991: 69-74. Compounds of the invention can be shown to have anti-angiogenic properties in an animal model described in Passaniti et al., Lab. Invest. 67: 519-528, 1992. Compounds of the invention can be shown to inhibit restenosis in a porcine restenosis model described in Schwartz et al., J. Am. College of Cardiology 19: 267-274, 1992. Compounds of the invention can be shown to inhibit retinopathy in a mouse retinopathy model described in Smith et al., Invest. Ophthalmolo. & Vis. Sci. 35: 101-111, 1994, inhibit.

Claims (17)

Compound of the formula EB- (Alk) _p -Q- (Alk) _q -AG or a pharmaceutically acceptable salt thereof, wherein p and q are each independently 0 or 1; each Alk is independently an alkyl radical; A and Q are each independently a bond, -C (X) -, -S (O) _t -, -S-, -O-, -N (R ₁ ) -, -C (Y) -N (R ₁ ) -, --N (R ₁ ) -C (Y) -, -S (O) _t --N (R ₁ ) -, --N (R ₁ ) -S (O) _t -, --N (R ₁ ) - C (Y) -N (R ₁ ) - or -N (R ₁ ) -S (O) _t -N (R ₁ ) - or a radical of cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which optionally with 1 to 3 radicals of R _{2 is} substituted; and B is a bond, -C (Y) -, -S (O) _t -, -S-, -O-, -N (R ₁ ) -, -C (Y) -N (R ₁ ) -, - N (R ₁ ) -C (Y) -, -S (O) _t -N (R ₁ ) -, -N (R ₁ ) -S (O) _t -, -N (R ₁ ) -C (Y ) -N (R ₁ ) - or -N (R ₁ ) -S (O) _t -N (R ₁ ) - or a radical of cycloalkyl, aryl, heterocyclyl or heteroaryl, each of them optionally having 1 to 3 R _{2 is} substituted by radicals; with the proviso that the total number of atoms connecting E to G directly over the shortest sequence is 3 to 12; each X is independently O or S; and each Y is independently O, S, N (R ₁ ) or N (CN); and each t is independently 1 or 2; each R _{1 is} independently a hydrogen or alkyl radical; R ₂ each independently represents a halogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, hydroxy, carboxy, cyano, azido, amidino, guanidino, nitro, amino, alkylamino or dialkylamino radical or two adjacent R ₂ radicals represent a methylenedioxy, ethylenedioxy or propylenedioxy radical; E is a radical -R ₃ , -NH-R ₃ , -NH-C (Y) -R ₃ , -C (Y) -NH-R ₃ , -NH-S (O) _t -R ₃ , -S ( O) _t -NH-R ₃ , -NH-C (Y) -NH-R ₃ , -NH-C (Y) -OR ₃ , -NH-S (O) _t -NH-R ₃ , -NH- Alkyl-C (Y) -R ₃ , -NH-alkyl-S (O) _t -R ₃ , -NH-alkyl-C (Y) -NH-R ₃ or -NH-alkyl-S (O) _t - NH-R ₃ means; R _{3 is} a radical of aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl wherein the aryl, heteroaryl and heterocyclyl radicals are optionally substituted with 1 to 3 radicals of R ₂ ; G is a remainder of the formulas

wherein W _{1 is} CR ₁₅ or N; W _{2 is} CR ₁₆ or N; W _{3 is} CR ₁₇ or N; and W _{4 is} CR ₁₈ or N; with the proviso that not more than 2 of W ₁ , W ₂ , W ₃ or W _{4 are} N; or G is a radical of the formula

wherein W _{1 is} CR ₁₅ ; W _{2 is} CR ₁₆ ; W _{3 is} CR ₁₇ ; and W _{4 is} CR ₁₈ ; Radicals of R ₁₅ , R ₁₇ and R _{18 are} each independently a radical of hydrogen, halogen, hydroxy, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, -CF ₃ or -OCF ₃ ; R _{16 is} a radical of hydrogen, halogen, hydroxyl, carboxy, cyano, amino -R ₉ , -S (O) _t -R ₉ , -OR ₉ , -N (R ₁ ) -R ₉ , -C (O) - N (R ₁ ) -R ₉ , -N (R ₁ ) -C (O) -H, -N (R ₁ ) -C (O) -R ₉ , -S (O) _t -N (R ₁ ) -R ₉ or -N (R ₁ ) -S (O) _t -R ₉ ; with the proviso that the total number of aryl, cycloalkyl, heteroaryl and heterocyclyl radicals in R ₁₅ , R ₁₆ , R ₁₇ and R _{18 is} 0 to 1; each R _{9 is} independently a radical of C ₁ -C ₄ alkyl, -CF ₃ , phenyl C ₁ -C ₄ alkyl or phenyl, wherein each phenyl radical is optionally substituted with 1 to 3 radicals of R ₂ ; X ₂ , X ₃ and X _{6 are} each independently a residue -CHR ₆ -; Z _{1 is} CR ₆ ; R ₁₀ and R _{12 are} each independently a hydrogen, hydroxy or C ₁ -C ₄ alkyl radical; each R _{6 is} independently a hydrogen, hydroxy or C ₁ -C ₄ alkyl radical; R _{4 is} a C ₁ -C ₄ alkyl substituted with carboxy, tetrazolyl or -CO ₂ R ₈ and optionally substituted with aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with 1 to 3 residues of R _{2 is} substituted; wherein R _{8 is} a C ₁ -C ₄ alkyl radical which is optionally substituted with a radical of aryl or heteroaryl having 5 to 10 ring members, wherein the aryl and heteroaryl radicals are optionally substituted by 1 to 3 radicals of R ₂ , wherein Alkyl ", alone or in combination, means a saturated or partially unsaturated (provided that at least two carbon atoms are present) straight-chain or branched alkyl radical; "Cycloalkyl", alone or in combination, refers to a saturated or partially unsaturated carbocyclic group. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each Alk is independently a C ₁ -C ₁₂ alkyl radical; A and Q are each independently a bond, -C (X) -, -S (O) _t -, -S-, -O-, -N (R ₁ ) -, -C (Y) -N (R ₁ ) -, -N (R ₁ ) -C (Y) -, S (O) _t -N (R ₁ ) -, -N (R ₁ ) -S (O) _t -, -N (R ₁ ) -C (Y) -N (R ₁ ) - or -N (R ₁ ) -S (O) _t -N (R ₁ ) - or a radical of C ₃ -C ₈ cycloalkyl, aryl, heterocyclyl having 5 to 8 ring members or heteroaryl of 5 to 10 ring members, each of which is optionally substituted with 1 to 3 residues of R ₂ ; and B is a bond, -C (Y) -, -S (O) _t -, -S-, -O-, -N (R ₁ ) -, -C (Y) -N (R ₁ ) -, - N (R ₁ ) -C (Y) -, -S (O) _t -N (R ₁ ) -, -N (R ₁ ) -S (O) _t -, -N (R ₁ ) -C (Y ) -N (R ₁ ) - or -N (R ₁ ) -S (O) _t -N (R ₁ ) - or a radical of C ₃ -C ₆ -cycloalkyl, aryl, heterocyclyl having 5 to 8 ring members or heteroaryl with 5 to 10 ring members, each of which is optionally substituted with 1 to 3 residues of R ₂ ; with the proviso that the total number of atoms connecting E to G directly over the shortest sequence is 3 to 12; each X is independently O or S; and each Y is independently O, S, N (R ₁ ) or N (CN); and each t is independently 1 or 2; each R _{1 is} independently a hydrogen or C ₁ -C ₄ alkyl radical; Radicals of R _{2 are} each independently a halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ haloal kyl- with 1 to 3 halogen radicals, C ₁ -C ₄ -haloalkoxy- with 1 to 3 halogen radicals, hydroxy, carboxy, cyano, azido, amidino, guanidino, nitro, amino, C ₁ -C _4- alkylamino or di (C ₁ -C ₄ -alkyl) amino or two adjacent R ₂ radicals represent a methylenedioxy, ethylenedioxy or propylenedioxy; E is a radical -R ₃ , -NH-R ₃ , -NH-C (Y) -R ₃ , -C (Y) -NH-R ₃ , -NH-S (O) _t -R ₃ , -S ( O) _t -NH-R ₃ , -NH-C (Y) -NH-R ₃ , -NH-C (Y) -OR ₃ , -NH-S (O) _t -NH-R ₃ , -NH- (C ₁ -C ₄ -alkyl) -C (Y) -R ₃ , -NH- (C ₁ -C ₄ -alkyl) -S (O) _t -R ₃ , -NH- (C ₁ -C ₄ -) alkyl) -C (Y) -NH-R ₃ or -NH- (C ₁ -C ₄ alkyl) -S (O) t-NH-R _3; R _{3 is} an aryl, aryl, C ₁ -C ₁₀ alkyl, heteroaryl, heteroaryl C ₁ -C ₁₀ alkyl, heterocyclyl or heterocyclyl C ₁ -C ₁₀ alkyl radical, wherein the heteroaryl and heterocyclyl radicals Have 5 to 15 ring members and the aryl, heteroaryl and heterocyclyl groups are optionally substituted with 1 to 3 residues of R ₂ . A compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein each Alk is independently a C ₁ -C ₈ alkyl radical; every XO is; and each Y is independently O, N (R ₁ ) or N (CN); and every t is 2; E is a radical -R ₃ , -NH-R ₃ , -NH-C (Y) -R ₃ , -C (Y) -NH-R ₃ , -S (O) _t -NH-R ₃ , -NH- C is (Y) -NH-R ₃ , -NH-C (Y) -OR ₃ or -NH- (C ₁ -C ₄ -alkyl) -C (Y) -NH-R ₃ ; R _{3 is} an aryl, aryl C ₁ -C ₁₀ alkyl, heteroaryl, heteroaryl C ₁ -C ₄ alkyl, heterocyclyl or heterocyclyl C ₁ -C ₄ alkyl radical wherein the heteroaryl and Heterocyclyl radicals have 5 to 15 ring members and the aryl, heteroaryl and heterocyclyl radicals are optionally substituted by 1 to 3 radicals of R ₂ . A compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein each Alk is independently a C ₁ -C ₆ alkyl radical; A and Q are each independently a bond, -C (O) -, -S (O) _t -, -O-, -N (R ₁ ) -, -C (Y) -N (R ₁ ) -, -N (R ₁ ) -C (Y) -, S (O) _t -N (R ₁ ) - or -N (R ₁ ) -S (O) _t - or a radical of C ₃ -C ₆ -cycloalkyl, phenyl Heterocyclyl having 5 to 6 ring members or heteroaryl having 5 to 6 ring members, each of which is optionally substituted with 1 to 3 residues of R ₂ ; and B is a bond, -C (Y) -, -S (O) _t -, -O- or -N (R ₁ ) - or a radical of phenyl, heterocyclyl having 5 to 6 ring members or heteroaryl having 5 to 6 ring members each of which is optionally substituted with 1 to 3 residues of R ₂ ; with the proviso that the total number of atoms connecting E to G directly over the shortest sequence is 4 to 9; R ₂ each independently represents a halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, -CF ₃ , -OCF ₃ , hydroxy, cyano , Nitro, amino, C ₁ -C ₄ alkylamino or di (C ₁ -C ₄ alkyl) amino; E is a radical -R ₃ , -NH-R ₃ , -NH-C (Y) -R ₃ , -C (Y) -NH-R ₃ , -NH-C (Y) -NH-R ₃ or -NH -C (Y) -OR ₃ means; R _{3 is} an aryl, aryl, C ₁ -C ₄ alkyl, heteroaryl or heteroaryl C ₁ -C ₄ alkyl radical in which the heteroaryl radical has from 5 to 15 ring members and the aryl and heteroaryl radicals are optionally substituted by 1 to 3 R ₂ radicals are substituted; W _{1 is} CR ₁₅ ; W _{2 is} CR ₁₆ ; W _{3 is} CR ₁₇ ; and W _{4 is} CR ₁₈ ; Radicals of R ₁₅ , R ₁₇ and R _{18 are} each independently a radical of hydrogen, halogen, hydroxy, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, -CF ₃ or -OCF ₃ ; R _{16 is} a radical of hydrogen, halogen, hydroxyl, carboxy, cyano, amino, -R ₉ , -S (O) _t -R ₉ , -OR ₉ , -N (R ₁ ) -R ₉ , -C (O) -N (R ₁ ) -R ₉ , -N (R ₁ ) -C (O) -H, -N (R ₁ ) -C (O) -R ₉ , -S (O) _t -N (R ₁ ) -R ₉ or -N (R ₁ ) -S (O) _t -R ₉ ; wherein each R _{9 is} independently a radical of C ₁ -C ₄ alkyl, -CF ₃ , phenyl-C ₁ -C ₄ alkyl or phenyl, wherein each phenyl radical is optionally substituted with 1 to 3 radicals of R ₂ ; X ₂ , X ₃ and X _{6 are} each independently a residue -CHR ₆ -; Z _{1 is} CR ₆ ; R ₁₀ and R _{12 are} each independently a hydrogen, hydroxy or C ₁ -C ₂ alkyl radical; wherein each R _{6 is} independently a hydrogen, hydroxy or C ₁ -C ₂ alkyl radical; and R _{4 is} a C ₁ -C ₄ alkyl radical substituted with a residue of carboxy or -CO ₂ R ₈ ; wherein R _{8 is} a C ₁ -C ₄ alkyl radical optionally substituted with a phenyl radical wherein the phenyl radical is optionally substituted with 1 to 3 R ₂ radicals. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein B represents a bond, -S (O) _t -, -O- or -N (R ₁ ) - or a phenyl radical optionally containing 1 to 3 residues of R ₂ is substituted; with the proviso that the total number of atoms connecting E to G directly across the shortest sequence is 4 to 7; each R _{1 is} independently a hydrogen or a methyl radical; Each R ₂ is independently halo, methyl, methoxy, -CF ₃ , -OCF ₃ , hydroxy, cyano, nitro, amino, C ₁ -C ₄ alkylamino or di (C ₁ -) C ₂ alkyl) amino group; E is a radical -R ₃ , -NH-R ₃ , -NH-C (NR ₁ ) -R ₁ , -C (NR ₁ ) -NH-R ₁ , -NH-C (NR ₁ ) -NH-R ₁ or -NH-C (NR ₁ ) -O-CH ₃ ; R _{3 is} a heteroaryl group having 5 to 15 ring members and is optionally substituted with 1 to 3 groups of R ₂ ; R ₁₅ , R ₁₇ and R _{18 are} each independently a radical of hydrogen, fluoro, chloro, bromo, hydroxy, cyano, methyl, Me thoxy, -CF ₃ or -CCF ₃ ; R _{16 is} a radical of hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, -R ₉ , -S (O) _t -R ₉ , -OR ₉ , -N (R ₁ ) -R ₉ , -C ( O) -N (R ₁ ) -R ₉ , -N (R ₁ ) -C (O) -H, -N (R ₁ ) -C (O) -R ₉ , -S (O) _t -N ( R ₁ ) -R ₉ or -N (R ₁ ) -S (O) _t -R ₉ ; wherein each R _{9 is} independently a radical of C ₁ -C ₄ alkyl, -CF ₃ , phenyl C ₁ -C ₂ alkyl or phenyl, wherein each phenyl radical is optionally substituted with 1 to 3 radicals of R ₂ ; each R _{6 is} a hydrogen radical; and R _{4 is} a C ₁ -C ₂ alkyl radical substituted with a residue of carboxy or -CO ₂ R ₈ ; wherein R _{8 is} a C ₁ -C ₂ alkyl radical. A compound according to claim 5, which is 2- (2- (N- (3- (2-pyridylamino) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- (2) 2- (N- (4- (2-pyridylamino) butyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- (2- (N- (5- 2-pyridylamino) pent-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- (2- (N-methyl-N- (4- (2 -pyridylamino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- (2- (N- (4- (2-pyridylamino) -trans -cyclohexyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- (2 - (((4- (2-pyridylamino) methyl) piperid-1-yl) carbonyl ) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- (2- (N- (3- (2-pyridylamino) methylphenyl) carbamoyl) -1H, 3H, 4H, 5H -benzo [e] azapin-5-yl) acetic acid, 2- (2- (N- (4 - ((6-methyl-2-pyridyl) amino) but-1-yl) carbamoyl) -1H, 3H, 4H , 5H-benzo [e] azapin-5-yl) acetic acid, 2- (2- (N- (4- (pyrimidin-2-ylamino) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H- benzo [e] azapin-5-yl) acetic acid, 2- (2- (N- (3- (6-amino-2-pyridyl) prop-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2 (2- (N- (3- (6- (tert-Butoxycarbonylamino) -2-pyridyl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid; 2- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) prop-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- (2 - (((4- (2-pyridylamino) but-1-yl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapine -5-yl) acetic acid, 2- (2 - (((3- (2-pyridylamino) prop-1-yl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl ) acetic acid, 2- (2- (2- (2 - ((2- (2-pyridylamino) ethyl) amino) acetyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- ( 2- (2 - ((3- (2-pyridylamino) prop-1-yl) amino) acetyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- (2- (2 - ((4- (2-pyridylamino) but-1-yl) amino) acetyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- (2 - (( N- (3- (2-pyridylamino) prop-1-yl) carbamoyl) methyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- (2- (4- 2-pyridylamino) but-1-oxycarbonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- (8-methoxy-2- (N- (4- (2-pyridylamino ) but-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5 yl) acetic acid, 2- (8-Fluoro-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) propyl) carbamoyl) -1H, 3H , 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetic acid, 2- (2 - ({N - (4- (2-pyridylamino) -prop-1-yl) carbamoyl} methyl) -3-oxo-1H , 4H, 5H-benzo (e) azepin-5-yl) acetic acid, 2- (3 - ({N- (4- (2-pyridylamino) but-1-yl) carbamoyl} methyl) -1H, 2H, 4H , 5H-benzo [d] azepin-1-yl) acetic acid, 2- (3 - {[N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] methyl} -1H, 2H, 4H, 5H-benzo [d] azepinyl) acetic acid, 2- (3- {N- (5- (2-pyridylamino) pent-1-yl) carbamoyl} -1H, 2H, 4H, 5H-benzo [d] azepinyl) acetic acid, 2- {3- (N- (3- (1,2,3,4-tetrahydropyridino [2,3-bpyridin-7-yl) propyl) carbamoyl] 1H, 2H, 4H, 5H-benzo [d] azepin-1-yl} acetic acid, 2- {3- (7- (2-pyridylamino) -heptanoyl) -1H, 2H, 4H, 5H-benzo [d] azepine -1-yl} acetic acid, 2- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) -propionic acid, 2- {2- [N- (methylethyl) -N- (2- (1,2,3,4-tetrahydropyridino [2,3-bpyridine] 7-yl) ethyl) carbamoyl] -1H, 3H, 4H, 5H benzo [e] azepin-5-yl] acetic acid, 2- (2-aza-2-cyano-1 ((1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl ) amino) vinyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- (2 - (((2- (1,2,3,4-tetrahydropyridino (2,3 -b) pyridin-7-yl) ethyl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 3- (2- (N- (2-) 2,3,4-Tetrahydropyridino (2,3-b) pyridin-7-yl) ethyl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) propionic acid, 2- 2- (N- (3- (2-Pyridylamino) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2 - ((5R) -2- (N-) (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) prop-1-yl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5 -yl) acetic acid, 2 - ((5R) -2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2 - ((5S) -2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2 - ((5S) -2- (4- (1,2,3, 4-tetrahydropyridino (2,3-b) pyridin-7-yl) butanoyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] aza pin-5-yl) acetic acid, 2- [2- (4- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) butanoyl) -1H, 3H, 4H, 5H- benzo [e] azepin-5-yl] acetic acid, 2- {2- [N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetic acid, 2- {2- [N- (methylethyl) -N- (2- (1,2,3 , 4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetic acid, 2- {2- [N- (methylethyl) -N- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-6-ylmethyl) carbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [ 1,2-a] azepin-5-yl} acetic acid, 2- {2- [N- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-6-ylmethyl) carbamoyl] -4H, 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl} acetic acid, 2- (2- {N -methyl-N- [3- (2-pyridylamino) -propyl] carbamoyl} -4H , 5H, 10H-benzo [d] imidazolo [1,2-a] azepin-5-yl) acetic acid, 2- (8-methoxy-2- (N- (3- (1,2,3,4-tetrahydropyridino [2,3, b] pyridin-7-yl) -propyl) -carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azaperhydroepin-5-yl) acetic acid, 2- (2- (N- (4- (2-one) 4,5-dihydroimidazo-2-yl) aminobut-1-yl) car bamoyl) -1H, 3H, 4H-5H-benzo [e] azapin-5-yl) acetic acid, 2- {8-chloro-2- [N- (3- (1,2,3,4-tetrahydropyridino [2 , 3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid, 2- {8-bromo-2- [N- (3 - (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid, 2 - {7,8-dibromo-2- [N- (3- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) propyl) carbamoyl] -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl} acetic acid, 2- (2- (N- (3- (6- (methylamino) -2-pyridyl) propyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- (2- (N- (2- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) - 1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- (3- (N- (2- (1,2,3,4-tetrahydropyridino (2,3-b) pyridine) 7-yl) propyl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 3- (2- (N- (2- (1,2,3,4 -Tetrahydropyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) propionic acid, 3- (2- (N- (3 - (1,2,3,4-tetrahydro pyridino (2,3-b) pyridin-7-yl) propyl) carbamoyl-1H, 3H, 4H, 5H-be nzo [e] azapin-5-yl) propionic acid, 3- (2- (N- (3- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) propyl) amino) sulfonyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) -propionic acid, 2- [3 - ({N- [5- (2-pyridylamino) -pentyl] -carbamoyl} -methyl) -1H, 2H , 4H, 5H-benzo [d] azepinyl] acetic acid, 2- [3- (2 - {[4- (2-pyridylamino) butyl] amino} acetyl) -1H, 2H, 4H, 5H-benzo [d] azepinyl ] acetic acid, 2- (2- {N- [3- (5-methyl-1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) -propyl] carbamoyl} -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl) acetic acid, 2- (3- {N- (2- (2-pyridylamino) ethyl) carbamoyl} -1H, 2H, 4H, 5H-benzo [d] azepinyl ) acetic acid, 2- {3- (N- (2- (1,2,3,4-tetrahydropyridino [2,3-b] pyridin-7-yl) ethyl) carbamoyl) -1H, 2H, 4H, 5H- benzo [d] azepin-1-yl} acetic acid, 2- (8-fluoro-2- (N- (2- (1,2,3,4-tetrahydropyridino (2,3-b) pyridin-7-yl) ethyl) carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azapin-5-yl) acetic acid, 2- [2- (N- {4 - [(4-methyl-2-pyridyl) amino] butyl} carbamoyl) -1H, 3H, 4H, 5H-benzo [e] azepin-5-yl] acetic acid or 2- {2- [N- (4 - {[benzylamino] carbonylamino) butyl) carbamoyl] -1H, 3H, 4H , 5H-benzo [e] azepin-5-y Is acetic acid or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound according to one the claims 1 to 6 and a pharmaceutically acceptable carrier. Use of the compound according to claims 1 to 6 for the preparation a drug used to treat a disease or disorder that is modulated by an integrin receptor. Use of the compound according to claim 8, wherein the integrin receptor is vitronectin receptor α _v β ₃ , α _v β ₅ or α _v β ₆ . Use of the composition according to claim 7 for the manufacture of a medicament for the treatment of a disease or disorder, which is modulated by an integrin receptor. Use of the composition according to claim 10, wherein the integrin receptor is vitronectin receptor α _v β ₃ , α _v β ₅ or α _v β ₆ . Use of the compound according to claims 1 to 6 for the preparation a drug for antagonizing an integrin receptor. Use of the compound according to claim 12, wherein the integrin receptor is vitronectin receptor α _v β ₃ , α _v β ₅ or α _v β ₆ . Use of the composition according to claim 7 for the manufacture of a medicament for antagonizing an integrin receptor. Use of the composition according to claim 14, wherein the integrin receptor is a vitronectin receptor α _v β ₃ , α _v β ₅ or α _v β ₆ . Use of the compound according to claims 1 to 6 for the preparation a drug for the treatment of atherosclerosis, restenosis, Inflammation, Wound healing, cancer, metastases, associated with bone resorption Diseases, diabetic retinopathy, macular degeneration, angiogenesis or viral infections. Use of the composition according to claim 7 for the manufacture of a medicament for prophylaxis or treatment of atherosclerosis, restenosis, inflammation, wound healing, cancer, Metastases, bone resorption-related diseases, diabetic Retinopathy, macular degeneration, angiogenesis or viral infections, comprising administering an effective amount of a composition according to claim 7.